Open access
1. Introduction
The FDA approvals of ipilimumab targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), pembrolizumab targeting the programmed cell death protein 1 (PD-1), BRAF inhibitors vemurafenib and dabrafenib, and MEK inhibitor trametinib represent significant milestones in more effective treatment of advanced melanoma. However, it is clear that the use of these single-agent therapies have limitation clinically. For example, ipilimumab only showed 4.5% objective response rate when used alone in a Phase II clinical trial [1]. The efficacy of vemurafenib lasts only 6.7 months before the disease relapses especially in patients with metastatic melanoma [2]. Therefore, rational combination approaches are strongly preferred in order to improve the overall patient progression-free survival (PFS), overcome or delay the development of multi-drug resistance and reduce the incidents of side effects [3-6].
In this chapter, we will summarize the emerging combination therapy approaches from both clinical trial and preclinical research in the past five years.
2. Combination of kinase inhibitors for melanoma treatment
2.1. Combined inhibitions targeting components within the Mitogen-Activated Protein Kinase (MAPK) signaling pathway
2.1.1. Targeting BRAF: Mechanism of action, toxicity and drug resistance
BRAF is a serine/threonine growth signal transduction protein kinase from RAF family which plays important roles in the RAS/RAF/MEK/ERK pathway and directs cell division, proliferation and secretion [7]. BRAF inhibitors (BRAFi) are ATP-competitive ligands which inactivate the function of BRAF protein by either stabilizing the inactive form of kinase domain (sorafenib) or preferentially inhibit the active form of the kinase (vemurafenib, dabrafenib) [8, 9]. Various mutations of
Figure 1.
The mechanisms of BRAF inhibitor vemurafenib (Vem) action, toxicity and the interaction between melanoma cells with T lymphocytes.
However, wide type BRAF melanoma tumors do not respond to vemurafenib or dabrafenib inhibition, although they are sensitive to the MEK inhibitors [9]. Paradoxically, in cells with RAS mutation and wild-type BRAF, treatment with vemurafenib or dabrafenib will promote the formation of BRAF-CRAF heterodimer and lead to the activation of subsequent MEK/ERK signaling and cell proliferation as shown in Figure 1 [5]. This mechanism is used to explain the observation of typical clinical side effects associated with the use of vemurafenib: nearly 25% of patients developed skin lesions and even cutaneous squamous cell carcinoma (CSCC). In addition,
2.1.2. Mechanisms of resistance to BRAF inhibition
In general, due to alternative pathway activations and inter-and intra-patients melanoma genetic heterogeneity, various mechanisms of resistance to BRAF inhibition have been identified [10, 16-19]. As we mentioned before, melanoma tumors bearing wide type BRAF are intrinsically resistant to vemurafenib and dabrafenib. Tumor micro-environment also contributes to the innate resistance to BRAF inhibition in melanoma. For example, stromal cells secrete hepatocyte growth factor (HGF), which activates the HGF-receptor MET, MAPK and PI3K-AKT pathways [20].
Eventually, nearly all BRAF mutated melanoma tumors develop acquired drug resistance upon treatment with BRAF inhibitors. The disease progression arises as early as two-month continuous treatment [18, 19]. The mechanisms of acquired resistance to BRAF inhibition can be generalized into two categories: BRAFV600E-bypass mechanisms and MAPK-bypass mechanisms.
First, the BRAFV600E-bypass mechanisms reactivate MAPK signaling and lead to ERK-dependent tumor cell survival and proliferation (Figure 2A). COT, which is coded by gene
Second, the MAPK-bypass mechanisms allow melanoma cells to escape from the cytotoxicity of BRAF or MEK inhibition through the activation of ERK-independent survival pathways (Figure 2B). The PI3K-AKT signaling pathway can be activated through the overexpression of receptor tyrosine kinases (RTKs), for example, insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) and platelet-derived growth factor receptor beta (PDGFRβ) [27]. The elevated levels of IGF-1R, PDGFRβ or HGF can also stimulate another receptor tyrosine kinase, MET, and increase the activity of PI3K. Phosphatase tensin (PTEN) is a negative regulator of PI3K. The PTEN loss-of-function mutation induces the resistance of BRAF inhibition and reduces the PFS of dabrafenib therapy in melanoma patients due to the PI3K activation [28]. Moreover, the upregulation of cyclin D1 can activate cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) and make melanoma cells less dependent on MAPK signaling in cell cycle progressing [29].
Figure 2.
The mechanisms of acquired resistance to BRAF inhibition.
Additionally, Jaehyuk Choi
2.1.3. Targeting MEK: Mechanism of action, toxicity and resistance
Trametinib, which is approved by FDA in May 2013 as a monotherapy agent against advanced melanoma with BRAFV600E and BRAFV600K mutations, is a first-in-class, orally available, allosteric (non-ATP-competitive) MEK1/MEK2 inhibitor (MEKi) [32, 33]. It selectively inhibits MEK, the down-stream kinase protein of RAF in the RAS-RAF-MEK-ERK pathway. As a result, melanoma cells with acquired resistance to BRAFi are commonly cross-resistant to MEKi such as trametinib or selumetinib, another selective allosteric MEKi [24, 34]. This mechanism explains the clinical trial results in which trametinib monotherapy fails to significantly benefit patients who have already developed acquired BRAFi resistance [35]. In contrast to the use of a BRAFi, no CSCC side effects are observed among the patients received trametinib treatment in clinical trials [13, 32]. However, similar to the use of vemurafenib, disease progression occurs within 6-7 months in patients receiving single-agent trametinib treatment [36]. Nevertheless, a retrospective analysis of 23 patients, who were first treated with MEKi and upon progression with a selective BRAFi, shows that the median time to progression (TTP) has been prolonged to 8.9 months from 4.8 months using a single-agent MEKi or 4.4 months for a single-agent BRAFi treatment, respectively [37]. However, a recent clinical trial indicated that if melanoma patients were treated with a BRAFi first then MEKi therapy, no confirmed response was observed [35]. This indicates that optimal treatment schedule and sequence is important for the melanoma therapy targeting the MAPK pathway.
2.1.4. Drug combination targeting MAPK pathway: From lab bench to clinical practice
Given that the mechanisms of tumor cells develop resistance to BRAFi partially by reactivating the ERK cascade and side effects such as CSCC are RAF-dependent, combining BRAFi with MEKi has attracted lots of research interest in order to further block the MAPK signaling pathway.
When it comes to the clinical trial data, the combined inhibition of BRAF-MEK has presented significant improvements of major patient benefits (PFS and overall survival). A phase I/II trial (ClinicalTrials.gov, NCT1072175) investigated the combination of oral dabrafenib (150 mg twice per day) plus oral trametinib (1 or 2 mg daily) (combination 150/1 and 150/2) versus monotherapy of dabrafenib (150 mg twice per day) over 108 metastatic melanoma patients bearing either V600E (92 patients) or V600K (16 patients) BRAF mutation [12, 36]. Median PFS in combination 150/2 group reached 9.4 months, compared to 5.8 months in the dabrafenib monotherapy group (hazard ratio 0.39, 95% confidence interval 0.25 to 0.62). The incidence of CSCC adverse events among combination 150/2 group is non-significantly lower than that among monotherapy group (7% versus 19%,
In addition, several ongoing phase I/II clinical trials now have shown that generally the combination of other BRAFi and MEKi is well tolerated in patients with or without receiving BRAFi treatment before (ClinicalTrials.gov, NCT01271803 vemurafenib (BRAFi)+cobimetinib (MEKi), NCT01543698 LGX818 (BRAFi)+MEK162 (MEKi)) [41-43] and overall response rate has increased comparing to the monotherapy groups, although the anti-tumor efficacy data haven’t been released.
2.2. Combination targeted therapy using Phosphatidylinositol 3-Kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) inhibitors
The activation of PI3K/AKT/mTOR pathway have been widely proved to be one of the major mechanisms of intrinsic or acquired resistance to both DNA-methylation agents (e.g. dacarbazine) and targeted BRAF inhibitor therapy (Figure 2). Some cell lines that are cross-resistant to both BRAFi and MEKi, are still sensitive to the inhibition of AKT/mTOR [34]. On the other hand, mechanistic study revealed evidences of a negative crosstalk between RAF/MEK/ERK and PI3K/AKT/mTOR pathways through RAS kinase. Therefore, when the downstream mTOR function is blocked, PI3K will be able to activate MAPK pathway via a switch of RAS [44, 45]. These investigations suggest a promising combination strategy of targeting MAPK pathway together with PI3K/AKT/mTOR cascade. Several preclinical studies widely proved that in MAPK inhibition sensitive melanoma cell lines, co-targeting PI3K/AKT/mTOR effectively induces cancer cell apoptosis with down-regulated anti-apoptotic BCL-2 family proteins [34, 46-48]. Such a co-targeting strategy can also postpone the emergence of acquired resistance to BRAFi dabrafenib mediated by PTEN mutation or disruption [49, 50]. Further, the dual inhibition of two pathways has successfully overcome NRAS mutation mediated resistance to MAPK blockade
A series of Phase I studies have evaluated the clinical relevance of the combination therapy which co-targets PI3K/AKT/mTOR and RAF/MEK/ERK pathways in terms of the incidence on severe side effect and anti-tumor efficacy in 236 patients. These patients have advanced cancers including melanoma, colorectal, pancreatic and non-small cell lung cancers. Results from three combination groups (AKTi MK2206+MEKi selumetinib, NCT01021748; AKTi GSK2141795+MEKi trametinib, NCT01138085; mTOR inhibitor everolimus+MEKi trametinib, NCT 00955773) are compared to the single treatment groups [53]. Overall, the combination therapy did not provide significant increase of tumor control rate (64.6% for combination, 52.7% for monotherapy,
2.3. Combining targeted therapy with anti-angiogenic agents
Melanoma is a vascular tumor. The abnormal expression of the epidermal growth factor (EGF) family protein and the up-regulation of EGFR-mediated alternative survival pathway have critically shaped the response of melanoma to the current chemotherapy agents [55-58]. In a recent study by Sun
Along with the rapid development of targeted melanoma therapeutics, the combined inhibition of VEGFR plus PDGFR or mTOR has shown synergy anti-tumor effects on mouse models of B16 metastatic melanoma without increasing toxicity [65, 66]. A large-scale, unbiased drug screening study, which aims to discover effective genotype selective combinatorial therapeutics of vemurafenib-resistant BRAF and RAS mutant melanoma, identifies a triple BRAF+EGFR+AKT inhibition as highly effective approach [3]. In the year of 2010, combination of bevacizumab with an mTOR inhibitor, everolimus, was evaluated in a phase II trial for patients with metastatic melanoma [67]. The treatment was well tolerated in most patients. Seven out of fifty-seven patients (12%) receiving combination therapy have shown major responses, although the median PFS was only 4 months. This year (2014), in a phase II trial that combines bevacizumab and sorafenib, which is an inhibitor of both RAF kinase and VEGFR-2/PDGFRβ signaling, no objective tumor responses are seen in all the fourteen patients receiving treatment [68, 69]. Interestingly, the median TTP of patients with low VEGF (<300 pg/ml) was longer than that of patients with high VEGF (50 weeks versus 15 weeks,
2.4. Combination therapy using targeted therapy with versatile chemotherapy agents
Since the abnormally activated (phosphorylation) of ERK and AKT constitutively exist in melanoma cells and promote the disease progression especially metastasis, blocking ERK or AKT pathway can sensitize the metastatic melanoma to the apoptosis induced by chemotherapeutic agents including cisplatin, temozolomide, DTIC and arsenite [70-72]. With the understanding of tumor biology about the programmed cell apoptosis and the rapid development of agents that can trigger the cell death process in melanoma, the combination of a MAPK inhibitor with a BCL-2 inhibitor (ABT-737 [73] or navitoclax [74]), or a MDM2 antagonist nutlin-3 [75], has synergistically induced apoptosis of melanoma
Due to the heterogenetic characteristics of melanoma disease, Vultur A
Metformin, a biguanide oral anti-diabetic drug, has been discovered with antitumor activity in various cancer types including melanoma. Although the exact mechanisms remain to be elucidated, accumulating data suggest that metformin can activate AMP-activated protein kinase (AMPK) and thus increase the activities of VEGF and ERK in BRAFV600E mutated melanoma cells [77]. AMPK negatively regulates malignant cell proliferation and viability [78]. The combination of vemurafenib and metformin has shown synergistic anti-proliferative effects on six out of eleven tested BRAFV600E melanoma cell lines [79]. Pilot clinical studies that evaluate the safety and efficacy of metformin combination therapies (plus dabrafenib or trametinib) are now recruiting patients (ClinicalTrials.gov, NCT0184000, NCT02143050).
Unlike the cutaneous melanoma, over-activation of MAPK pathway in uveal melanoma is associated GNAQ or GNA11 mutations instead of BRAF or RAS mutations [80]. Protein kinase C (PKC) inhibitors such as enzastaurin or AEB071 induce apoptosis in GNAQ-mutant but not in GNAQ wild type uveal melanoma cells [81]. The level of ERK phosphorylation also decreases in these cells when they are treated using PKC inhibitors [81]. Chen
Understanding the mechanisms of resistance to MAPK inhibition in melanoma can lead to rational combination designs in order to overcome acquired drug resistance to BRAF inhibitors. For example, our lab recently identified a synergistic combination in which a novel tubulin inhibitor ABI-274 combined with vemurafenib could overcome the acquired vemurafenib-resistance [83]. This combination treatment effectively arrested the vemurafenib-resistant melanoma cells in both G0/G1 and G2/M phases and induced strong apoptosis through the down-regulation of AKT phosphorylation. In addition, the combination of a MEKi (TAK-733) with an Hsp90 inhibitor (ganetespib) induces tumor regressions in vemurafenib-resistant xenograft models also through the depletion of AKT signaling [84]. With the finding that up-regulated cyclin D1 expression is critical for the survival of vemurafenib-resistant cells, a selective inhibitor of cyclin dependent kinase (CDK) 4/6, LY2835219, has been reported to overcome the reactivation of MAPK signaling in vemurafenib-resistant BRAFV600E melanoma [85].
3. Combinations involving immunotherapy in melanoma treatment
3.1. Combined blockade of immuno-checkpoints
Given the unsatisfactory results of cytokine-based melanoma immunotherapy (recombinant interferon-α 2b and high dose interleukin-2) in the past decade, the development and approval of ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody) in 2013 have marked a breakthrough of immune-checkpoints blockade therapy [86]. CTLA-4 (CD152) expresses on the surface of active T-lymphocytes and inhibits the initial T-cell proliferation and migration to the tumor tissue [87]. CTLA-4 antibodies preferentially target the suppressive regulatory T cells and prevent them from being hijacked by tumors [88]. In a double-blinded phase III study in 676 patients with pretreated and refractory metastatic melanoma, ipilimumab at the dose of 3 mg/kg achieved a median OS of 10 months [86]. In a meta-Kaplan-Meier-analysis of data collected from 1,861 melanoma patients in a clinical trial, a plateau of survival curve starts from around 3 years after ipilimumab treatment with follow-up extends as long as ten years, indicating a long-term survival benefits of ipilimumab therapy (ClinicalTrials.gov, NCT01844505). In addition, ipilimumab showed good tolerance and efficacy in several other clinical trials in which it was combined with a standard chemotherapy agent such as dacarbazine, fotemustine or temozolomide [89].
Another success of immune-check point blockade strategy is the development of anti-programmed death-1 (PD-1) antibodies, represented by pembrolizumab (MK-3475) and nivolumab [90, 91]. Pembrolizumab, as the first-in-class PD-1 inhibitor, has obtained FDA approval in September 2014 for patients with advanced or unresectable melanoma. The cDNA of PD-1 (CD279) is first cloned in programmed death T cells although PD-1 itself does not directly induce apoptosis. PD-1 is over-expressed on the surface of dysfunctional activated T-cells and contributes to the maintenance of T cell dysfunction (exhaust) phenotype and proliferation disability in the tumor site [92]. Two counter receptors of PD-1 have been identified: PD-L1 and PD-L2. PD-L1 is more frequently and exclusively expressed in various tumor cells; therefore, antibodies targeting PD-L1 (MPDL3280A and BMS-936559) also have anti-tumor activity in advanced cancer including melanoma [91, 93]. The PD-1-PD-L1 ligation retards the recognition and destroying of tumor cells by CD8+cytotoxic T-lymphocytes [87]. As a result, blocking PD-1 or PD-L1 will reverse the cancer cell immune escape. Because both CTLA-4 and PD-1 are key negative receptors that cooperatively modulate the adaptive immune response in tumor progression, their combination has been shown to be synergistic in B16 melanoma tumors without overt toxicity [94].
In a cohort phase I trial that studied the concurrent administration of ipilimumab and nivolumab to 53 patients with advanced, treatment-resistant melanoma, more than 80% tumor reduction was observed in 30% patients after 12 weeks treatment at the maximum tolerated dose. Twenty-one out of fifty-three patients had objective responses and over 80% of these patients had tumor regression. Grade 3/4 adverse events are diagnosed in 53% patients but the toxicities are manageable with immune-suppressants [95]. Consequential trials with more enrollment number of patients are necessary to further evaluate the safety and efficacy of this promising double immune-checkpoints blockage therapy comparing with each of its monotherapy regiments.
Finally, combinatorial clinical trials using ipilimumab with other immunotherapy agents have shown some favorable therapeutic benefits. For example, combination of ipilimumab with peginterferon α-2b (pegylated interferon α-2b) in patients with unresectable melanoma both demonstrated significant increase of response rate and OS comparing with the monotherapy arm [96, 97] in recent phase I trials.
3.2. Combined therapy inhibiting both immuno-checkpoint and MAPK signaling pathway
Checkpoint blockade immunotherapy and MAPK targeted chemotherapy have distinct clinical profiles. For example, targeted therapy has relative higher initial response rate (~60% for BRAFi) with rapid onset of effect, but its efficacy restrictively rely on the continuous treatment and the therapeutic response is usually not durable due to the quick development of acquired drug resistance. In contrast, immunotherapy has much a lower response rate (4.5% for ipilimumab), delayed onset of effect and difficulty in predicting patient outcome, but it has shown potentially durable responses and long-term survival benefit even off treatment. In addition, since the MAPK pathway is not required in the process of anti-tumor immune response, blocking MAPK signaling should not interfere with the efficacy of checkpoint blockade immunotherapy. Therefore, it seems very rational that the combination of a MAPKi and an immunotherapy agent such as ipilimumab or pembrolizumab can maximize the therapeutic benefits in advance melanoma.
Interestingly, BRAF and MEK inhibition displayed an “endogenous vaccine-like” effects in melanoma cells [98]. Cytotoxic agents like BRAFi induce tumor cell death and promote the uptake and presentation of tumor antigens to the effector immune cells (T cells and B cells) through antigen-presenting cells [54]. MEK inhibition, BRAFV600E RNA silencing or BRAF inhibition by PLX4720 increases the CD4+ and CD8+ lymphocytes mediated T-cell infiltration and reduce the level of immune-suppressants including IL-6, IL-10 or VEGF [99-101] in mice. The expression of PD-L1 is found to be elevated in BRAFi-resistant melanoma cells and it is mediated through the off-target activity of BRAFi in JUN and STAT3 signaling [102]. However, Vella
As for the clinical practice, dose-limiting hepatotoxicity issues have led to the premature termination of the first phase I study on combination of ipilimumab with vemurafenib (ClinicalTrials.gov, NCT01400451). This signified the complexity of adverse effect in combined therapy of immune-regulating agents and kinase inhibitors. Another phase I study of ipilimumab plus dabrafenib, or ipilimumab plus the combination of dabrafenib with trametinib is still active and a phase II study is exploring the safety and efficacy of sequential administration of vemurafenib followed by ipilimumab (ClinicalTrials.gov, NCT01767454, NCT01673854). The data of these most recent trials will be released in the near future.
4. Conclusions
Extensive efforts and remarkable progresses have been made to discover and investigate rational approaches in combination melanoma therapy since the recent approval of MAPKi and immune checkpoints blockade antibodies. A number of new targeted or immune drugs for metastatic melanoma are currently under commercial development or late stage clinical trials, some of which will likely be approved in the next few years. Quality of life for many melanoma patients has been dramatically increased. However, significant challenges still remain. While some clinical evidence has really raised the expectation of survivals for patients with advanced melanoma, the benefits of combination therapy are usually accompanied by limitations. Comprehensive genetic profile and tailored patient matching is essential for targeted therapy, while biomarkers are critical to predict the patient immunotherapy response. Drug-related toxicity for combination treatment usually is not a simple one-plus-one situation, and potential drug-drug interactions, especially the combination of a targeted agent with an immunotherapeutic agent must be carefully evaluated in order to achieve both fast and durable responses. Adverse effects should be closely monitored and potential alternative dosing regiments is worth further exploration. Optimized dose schedule may help to delay the resistance development and reduce the frequency of adverse effect. For example, intermittent doses of BRAFi was able to enhance the tolerance in combination with immunotherapy, decrease the paradoxical MAPK activation, which might be the main cause of severe toxicity in clinical trial [104]. Solid evidence of synergistic combination in preclinical research must be established before clinical trial conduction. In fact, with the relatively large number of available targeted agents and immunotherapeutic agents for metastatic melanoma, the huge number of possible drug combinations coupled with dosing sequences or schedules already presents a significant challenge in designing proper clinical trials. To test all the possible drug combinations along with different dosing sequences clinically will not only have low benefits to patients, but is also a huge financial burden to the society. Carefully designed, predictive preclinical studies will be essential to provide critical supports for rational prioritization of clinical trials using drug combinations. Finally, clear understandings of various combination mechanisms and patient genetic profiles are critically important for the development of new combination approaches, prediction of expected therapy response and potential side effects. With the rapid advances in this field, it is likely that optimal combination treatments will great improve the management of advanced melanoma in cancer patients.
Abbreviations
AMPK: 5' adenosine monophosphate-activated protein kinase
BRAF: B-Raf protein
BRAFi: BRAF inhibitor
CDK: Cyclin dependent kinase
CR: Complete response
CTLA-4: Cytotoxic T lymphocyte-associated antigen 4
ERK: Extracellular signal-regulated kinase
HR: Hazard ratio
JNK: c-Jun N-terminal kinase
MAPK: Mitogen-activated protein kinase
MEKi: MEK inhibitor
MHC: Membrane histocompatibility complex
mTOR: Mammalian target of rapamycin
ORR: Overall response rate
OS: Overall survival
PD-1: Programmed cell death 1
PD-L1: Programmed cell death 1 ligand 1
PDGFR: Platete-derived growth factor receptor
PFS: Progression-free survival
PI3K: Phosphoinositide 3-kinase
PKC: Protein kinase C
PR: Partial response
RTKs: Receptor tyrosine kinases
TCR: T cell receptor
VEGF: Vascular endothelial growth factor
VEGFR: Vascular endothelial growth factor receptor
Acknowledgments
This work was supported by NIH grants R01CA148706. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Jin Wang acknowledges the support of the Alma and Hal Reagan Fellowship.
References
- 1.
Hersh, E.M.; O'Day, S.J.; Powderly, J.; Khan, K.D.; Pavlick, A.C.; Cranmer, L.D.; Samlowski, W.E.; Nichol, G.M.; Yellin, M.J.; Weber, J.S., A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Investigational new drugs, 2011,29 , (3), 489-498. - 2.
Sosman, J.A.; Kim, K.B.; Schuchter, L.; Gonzalez, R.; Pavlick, A.C.; Weber, J.S.; McArthur, G.A.; Hutson, T.E.; Moschos, S.J.; Flaherty, K.T.; Hersey, P.; Kefford, R.; Lawrence, D.; Puzanov, I.; Lewis, K.D.; Amaravadi, R.K.; Chmielowski, B.; Lawrence, H.J.; Shyr, Y.; Ye, F.; Li, J.; Nolop, K.B.; Lee, R.J.; Joe, A.K.; Ribas, A., Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. The New England journal of medicine, 2012,366 , (8), 707-714. - 3.
Al-Lazikani, B.; Workman, P., Unpicking the combination lock for mutant BRAF and RAS melanomas. Cancer discovery, 2013,3 , (1), 14-19. - 4.
Hu-Lieskovan, S.; Robert, L.; Homet Moreno, B.; Ribas, A., Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014,32 , (21), 2248-2254. - 5.
Nijenhuis, C.M.; Haanen, J.B.; Schellens, J.H.; Beijnen, J.H., Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma? Cancer treatment reviews, 2013,39 , (4), 305-312. - 6.
Voskoboynik, M.; Arkenau, H.T., Combination therapies for the treatment of advanced melanoma: a review of current evidence. Biochemistry research international, 2014,2014 , 307059. - 7.
Wan, P.T.; Garnett, M.J.; Roe, S.M.; Lee, S.; Niculescu-Duvaz, D.; Good, V.M.; Jones, C.M.; Marshall, C.J.; Springer, C.J.; Barford, D.; Marais, R.; Cancer Genome, P., Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 2004,116 , (6), 855-867. - 8.
Tsai, J.; Lee, J.T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.; Haass, N.K.; Sproesser, K.; Li, L.; Smalley, K.S.; Fong, D.; Zhu, Y.L.; Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.; Suzuki, Y.; Luu, C.; Settachatgul, C.; Shellooe, R.; Cantwell, J.; Kim, S.H.; Schlessinger, J.; Zhang, K.Y.; West, B.L.; Powell, B.; Habets, G.; Zhang, C.; Ibrahim, P.N.; Hirth, P.; Artis, D.R.; Herlyn, M.; Bollag, G., Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proceedings of the National Academy of Sciences of the United States of America, 2008,105 , (8), 3041-3046. - 9.
King, A.J.; Arnone, M.R.; Bleam, M.R.; Moss, K.G.; Yang, J.; Fedorowicz, K.E.; Smitheman, K.N.; Erhardt, J.A.; Hughes-Earle, A.; Kane-Carson, L.S.; Sinnamon, R.H.; Qi, H.; Rheault, T.R.; Uehling, D.E.; Laquerre, S.G., Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PloS one, 2013,8 , (7), e67583. - 10.
Solit, D.B.; Rosen, N., Towards a unified model of RAF inhibitor resistance. Cancer discovery, 2014,4 , (1), 27-30. - 11.
Hooijkaas, A.; Gadiot, J.; Morrow, M.; Stewart, R.; Schumacher, T.; Blank, C.U., Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma. Oncoimmunology, 2012,1 , (5), 609-617. - 12.
Menzies, A.M.; Long, G.V., Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 2014,20 , (8), 2035-2043. - 13.
Carlino, M.S.; Gowrishankar, K.; Saunders, C.A.; Pupo, G.M.; Snoyman, S.; Zhang, X.D.; Saw, R.; Becker, T.M.; Kefford, R.F.; Long, G.V.; Rizos, H., Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Molecular cancer therapeutics, 2013,12 , (7), 1332-1342. - 14.
Klein, O.; Clements, A.; Menzies, A.M.; O'Toole, S.; Kefford, R.F.; Long, G.V., BRAF inhibitor activity in V600R metastatic melanoma. European journal of cancer, 2013,49 , (5), 1073-1079. - 15.
Vin, H.; Ojeda, S.S.; Ching, G.; Leung, M.L.; Chitsazzadeh, V.; Dwyer, D.W.; Adelmann, C.H.; Restrepo, M.; Richards, K.N.; Stewart, L.R.; Du, L.; Ferguson, S.B.; Chakravarti, D.; Ehrenreiter, K.; Baccarini, M.; Ruggieri, R.; Curry, J.L.; Kim, K.B.; Ciurea, A.M.; Duvic, M.; Prieto, V.G.; Ullrich, S.E.; Dalby, K.N.; Flores, E.R.; Tsai, K.Y., BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling. eLife, 2013,2 , e00969. - 16.
Roesch, A., Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma. Oncogene, 2014. - 17.
Yancovitz, M.; Litterman, A.; Yoon, J.; Ng, E.; Shapiro, R.L.; Berman, R.S.; Pavlick, A.C.; Darvishian, F.; Christos, P.; Mazumdar, M.; Osman, I.; Polsky, D., Intra-and inter-tumor heterogeneity of BRAF(V600E))mutations in primary and metastatic melanoma. PloS one, 2012,7 , (1), e29336. - 18.
Little, A.S.; Smith, P.D.; Cook, S.J., Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene, 2013,32 , (10), 1207-1215. - 19.
Tentori, L.; Lacal, P.M.; Graziani, G., Challenging resistance mechanisms to therapies for metastatic melanoma. Trends in pharmacological sciences, 2013,34 , (12), 656-666. - 20.
Straussman, R.; Morikawa, T.; Shee, K.; Barzily-Rokni, M.; Qian, Z.R.; Du, J.; Davis, A.; Mongare, M.M.; Gould, J.; Frederick, D.T.; Cooper, Z.A.; Chapman, P.B.; Solit, D.B.; Ribas, A.; Lo, R.S.; Flaherty, K.T.; Ogino, S.; Wargo, J.A.; Golub, T.R., Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature, 2012,487 , (7408), 500-504. - 21.
Johannessen, C.M.; Boehm, J.S.; Kim, S.Y.; Thomas, S.R.; Wardwell, L.; Johnson, L.A.; Emery, C.M.; Stransky, N.; Cogdill, A.P.; Barretina, J.; Caponigro, G.; Hieronymus, H.; Murray, R.R.; Salehi-Ashtiani, K.; Hill, D.E.; Vidal, M.; Zhao, J.J.; Yang, X.; Alkan, O.; Kim, S.; Harris, J.L.; Wilson, C.J.; Myer, V.E.; Finan, P.M.; Root, D.E.; Roberts, T.M.; Golub, T.; Flaherty, K.T.; Dummer, R.; Weber, B.L.; Sellers, W.R.; Schlegel, R.; Wargo, J.A.; Hahn, W.C.; Garraway, L.A., COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 2010,468 , (7326), 968-972. - 22.
Wagle, N.; Emery, C.; Berger, M.F.; Davis, M.J.; Sawyer, A.; Pochanard, P.; Kehoe, S.M.; Johannessen, C.M.; Macconaill, L.E.; Hahn, W.C.; Meyerson, M.; Garraway, L.A., Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2011,29 , (22), 3085-3096. - 23.
Poulikakos, P.I.; Zhang, C.; Bollag, G.; Shokat, K.M.; Rosen, N., RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature, 2010,464 , (7287), 427-430. - 24.
Gowrishankar, K.; Snoyman, S.; Pupo, G.M.; Becker, T.M.; Kefford, R.F.; Rizos, H., Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. The Journal of investigative dermatology, 2012,132 , (7), 1850-1859. - 25.
Carlino, M.S.; Todd, J.R.; Gowrishankar, K.; Mijatov, B.; Pupo, G.M.; Fung, C.; Snoyman, S.; Hersey, P.; Long, G.V.; Kefford, R.F.; Rizos, H., Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma. Molecular oncology, 2014,8 , (3), 544-554. - 26.
Sanchez-Laorden, B.; Viros, A.; Girotti, M.R.; Pedersen, M.; Saturno, G.; Zambon, A.; Niculescu-Duvaz, D.; Turajlic, S.; Hayes, A.; Gore, M.; Larkin, J.; Lorigan, P.; Cook, M.; Springer, C.; Marais, R., BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Science signaling, 2014,7 , (318), ra30. - 27.
Su, F.; Bradley, W.D.; Wang, Q.; Yang, H.; Xu, L.; Higgins, B.; Kolinsky, K.; Packman, K.; Kim, M.J.; Trunzer, K.; Lee, R.J.; Schostack, K.; Carter, J.; Albert, T.; Germer, S.; Rosinski, J.; Martin, M.; Simcox, M.E.; Lestini, B.; Heimbrook, D.; Bollag, G., Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer research, 2012,72 , (4), 969-978. - 28.
Nathanson, K.L.; Martin, A.M.; Wubbenhorst, B.; Greshock, J.; Letrero, R.; D'Andrea, K.; O'Day, S.; Infante, J.R.; Falchook, G.S.; Arkenau, H.T.; Millward, M.; Brown, M.P.; Pavlick, A.; Davies, M.A.; Ma, B.; Gagnon, R.; Curtis, M.; Lebowitz, P.F.; Kefford, R.; Long, G.V., Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clinical cancer research : an official journal of the American Association for Cancer Research, 2013,19 , (17), 4868-4878. - 29.
Smalley, K.S.; Lioni, M.; Dalla Palma, M.; Xiao, M.; Desai, B.; Egyhazi, S.; Hansson, J.; Wu, H.; King, A.J.; Van Belle, P.; Elder, D.E.; Flaherty, K.T.; Herlyn, M.; Nathanson, K.L., Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Molecular cancer therapeutics, 2008,7 , (9), 2876-2883. - 30.
Choi, J.; Landrette, S.F.; Wang, T.; Evans, P.; Bacchiocchi, A.; Bjornson, R.; Cheng, E.; Stiegler, A.L.; Gathiaka, S.; Acevedo, O.; Boggon, T.J.; Krauthammer, M.; Halaban, R.; Xu, T., Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors. Pigment cell & melanoma research, 2014,27 , (2), 253-262. - 31.
Wu, C.P.; Sim, H.M.; Huang, Y.H.; Liu, Y.C.; Hsiao, S.H.; Cheng, H.W.; Li, Y.Q.; Ambudkar, S.V.; Hsu, S.C., Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Biochemical pharmacology, 2013,85 , (3), 325-334. - 32.
Flaherty, K.T.; Robert, C.; Hersey, P.; Nathan, P.; Garbe, C.; Milhem, M.; Demidov, L.V.; Hassel, J.C.; Rutkowski, P.; Mohr, P.; Dummer, R.; Trefzer, U.; Larkin, J.M.; Utikal, J.; Dreno, B.; Nyakas, M.; Middleton, M.R.; Becker, J.C.; Casey, M.; Sherman, L.J.; Wu, F.S.; Ouellet, D.; Martin, A.M.; Patel, K.; Schadendorf, D.; Group, M.S., Improved survival with MEK inhibition in BRAF-mutated melanoma. The New England journal of medicine, 2012,367 , (2), 107-114. - 33.
Wright, C.J.; McCormack, P.L., Trametinib: first global approval. Drugs, 2013,73 , (11), 1245-1254. - 34.
Atefi, M.; von Euw, E.; Attar, N.; Ng, C.; Chu, C.; Guo, D.; Nazarian, R.; Chmielowski, B.; Glaspy, J.A.; Comin-Anduix, B.; Mischel, P.S.; Lo, R.S.; Ribas, A., Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway. PloS one, 2011,6 , (12), e28973. - 35.
Kim, K.B.; Kefford, R.; Pavlick, A.C.; Infante, J.R.; Ribas, A.; Sosman, J.A.; Fecher, L.A.; Millward, M.; McArthur, G.A.; Hwu, P.; Gonzalez, R.; Ott, P.A.; Long, G.V.; Gardner, O.S.; Ouellet, D.; Xu, Y.; DeMarini, D.J.; Le, N.T.; Patel, K.; Lewis, K.D., Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2013,31 , (4), 482-489. - 36.
Flaherty, K.T.; Infante, J.R.; Daud, A.; Gonzalez, R.; Kefford, R.F.; Sosman, J.; Hamid, O.; Schuchter, L.; Cebon, J.; Ibrahim, N.; Kudchadkar, R.; Burris, H.A., 3rd; Falchook, G.; Algazi, A.; Lewis, K.; Long, G.V.; Puzanov, I.; Lebowitz, P.; Singh, A.; Little, S.; Sun, P.; Allred, A.; Ouellet, D.; Kim, K.B.; Patel, K.; Weber, J., Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. The New England journal of medicine, 2012,367 , (18), 1694-1703. - 37.
Goldinger, S.M.; Zimmer, L.; Schulz, C.; Ugurel, S.; Hoeller, C.; Kaehler, K.C.; Schadendorf, D.; Hassel, J.C.; Becker, J.; Hauschild, A.; Dummer, R.; Dermatology Cooperative Oncology, G., Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients. European journal of cancer, 2014,50 , (2), 406-410. - 38.
Greger, J.G.; Eastman, S.D.; Zhang, V.; Bleam, M.R.; Hughes, A.M.; Smitheman, K.N.; Dickerson, S.H.; Laquerre, S.G.; Liu, L.; Gilmer, T.M., Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Molecular cancer therapeutics, 2012,11 , (4), 909-920. - 39.
Nakamura, A.; Arita, T.; Tsuchiya, S.; Donelan, J.; Chouitar, J.; Carideo, E.; Galvin, K.; Okaniwa, M.; Ishikawa, T.; Yoshida, S., Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer research, 2013,73 , (23), 7043-7055. - 40.
Lee, C.I.; Menzies, A.M.; Haydu, L.E.; Azer, M.; Clements, A.; Kefford, R.F.; Long, G.V., Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma. Melanoma research, 2014. - 41.
Ribas, A.; Gonzalez, R.; Pavlick, A.; Hamid, O.; Gajewski, T.F.; Daud, A.; Flaherty, L.; Logan, T.; Chmielowski, B.; Lewis, K.; Kee, D.; Boasberg, P.; Yin, M.; Chan, I.; Musib, L.; Choong, N.; Puzanov, I.; McArthur, G.A., Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. The lancet oncology, 2014,15 , (9), 954-965. - 42.
Kefford, R.; Miller, W.H.; Tan, D.S.W.; Sullivan, R.J.; Long, G.; Dienstmann, R.; Tai, W.M.D.; Flaherty, K.; Stutvoet, S.; Schumacher, K.M.; Wandel, S.; De Parseval, L.A.; Tabernero, J., Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors. Journal of Clinical Oncology, 2013, 31, (15_supplement), abstract 9029. - 43.
Dummer, R.; Robert, C.; Nyakas, M.; McArthur, G.A.; Kudchadkar, R.R.; Gomez-Roca, C.; Sullivan, R.J.; Flaherty, K.; Murer, C.; Michel, D.; Tang, Z.W.; De Parseval, L.A.; Delord, J.P., Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma. Journal of Clinical Oncology, 2013,31 , (15). - 44.
Carracedo, A.; Pandolfi, P.P., The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene, 2008,27 , (41), 5527-5541. - 45.
Villanueva, J.; Vultur, A.; Lee, J.T.; Somasundaram, R.; Fukunaga-Kalabis, M.; Cipolla, A.K.; Wubbenhorst, B.; Xu, X.; Gimotty, P.A.; Kee, D.; Santiago-Walker, A.E.; Letrero, R.; D'Andrea, K.; Pushparajan, A.; Hayden, J.E.; Brown, K.D.; Laquerre, S.; McArthur, G.A.; Sosman, J.A.; Nathanson, K.L.; Herlyn, M., Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer cell, 2010,18 , (6), 683-695. - 46.
Lasithiotakis, K.G.; Sinnberg, T.W.; Schittek, B.; Flaherty, K.T.; Kulms, D.; Maczey, E.; Garbe, C.; Meier, F.E., Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. The Journal of investigative dermatology, 2008,128 , (8), 2013-2023. - 47.
Niessner, H.; Beck, D.; Sinnberg, T.; Lasithiotakis, K.; Maczey, E.; Gogel, J.; Venturelli, S.; Berger, A.; Mauthe, M.; Toulany, M.; Flaherty, K.; Schaller, M.; Schadendorf, D.; Proikas-Cezanne, T.; Schittek, B.; Garbe, C.; Kulms, D.; Meier, F., The farnesyl transferase inhibitor lonafarnib inhibits mTOR signaling and enforces sorafenib-induced apoptosis in melanoma cells. The Journal of investigative dermatology, 2011,131 , (2), 468-479. - 48.
Khalili, J.S.; Yu, X.; Wang, J.; Hayes, B.C.; Davies, M.A.; Lizee, G.; Esmaeli, B.; Woodman, S.E., Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ-and GNA11-dependent manner. Clinical cancer research : an official journal of the American Association for Cancer Research, 2012,18 , (16), 4345-4355. - 49.
Lassen, A.; Atefi, M.; Robert, L.; Wong, D.J.; Cerniglia, M.; Comin-Anduix, B.; Ribas, A., Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma. Molecular cancer, 2014,13 , 83. - 50.
Byron, S.A.; Loch, D.C.; Wellens, C.L.; Wortmann, A.; Wu, J.; Wang, J.; Nomoto, K.; Pollock, P.M., Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. Molecular cancer, 2012,11 , 75. - 51.
Posch, C.; Moslehi, H.; Feeney, L.; Green, G.A.; Ebaee, A.; Feichtenschlager, V.; Chong, K.; Peng, L.; Dimon, M.T.; Phillips, T.; Daud, A.I.; McCalmont, T.H.; LeBoit, P.E.; Ortiz-Urda, S., Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America, 2013,110 , (10), 4015-4020. - 52.
Shi, H.; Kong, X.; Ribas, A.; Lo, R.S., Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer research, 2011,71 , (15), 5067-5074. - 53.
Shimizu, T.; Tolcher, A.W.; Papadopoulos, K.P.; Beeram, M.; Rasco, D.W.; Smith, L.S.; Gunn, S.; Smetzer, L.; Mays, T.A.; Kaiser, B.; Wick, M.J.; Alvarez, C.; Cavazos, A.; Mangold, G.L.; Patnaik, A., The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 2012,18 , (8), 2316-2325. - 54.
Frederick, D.T.; Piris, A.; Cogdill, A.P.; Cooper, Z.A.; Lezcano, C.; Ferrone, C.R.; Mitra, D.; Boni, A.; Newton, L.P.; Liu, C.W.; Peng, W.Y.; Sullivan, R.J.; Lawrence, D.P.; Hodi, F.S.; Overwijk, W.W.; Lizee, G.; Murphy, G.F.; Hwu, P.; Flaherty, K.T.; Fisher, D.E.; Wargo, J.A., BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma. Clinical Cancer Research, 2013,19 , (5), 1225-1231. - 55.
Lev, D.C.; Ruiz, M.; Mills, L.; McGary, E.C.; Price, J.E.; Bar-Eli, M., Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Molecular cancer therapeutics, 2003,2 , (8), 753-763. - 56.
Ghosh, S.; Maity, P., Augmented antitumor effects of combination therapy with VEGF antibody and cisplatin on murine B16F10 melanoma cells. International immunopharmacology, 2007,7 , (13), 1598-1608. - 57.
Sini, P.; Samarzija, I.; Baffert, F.; Littlewood-Evans, A.; Schnell, C.; Theuer, A.; Christian, S.; Boos, A.; Hess-Stumpp, H.; Foekens, J.A.; Setyono-Han, B.; Wood, J.; Hynes, N.E., Inhibition of multiple vascular endothelial growth factor receptors (VEGFR) blocks lymph node metastases but inhibition of VEGFR-2 is sufficient to sensitize tumor cells to platinum-based chemotherapeutics. Cancer research, 2008,68 , (5), 1581-1592. - 58.
Terheyden, P.; Hofmann, M.A.; Weininger, M.; Brocker, E.B.; Becker, J.C., Anti-vascular endothelial growth factor antibody bevacizumab in conjunction with chemotherapy in metastasising melanoma. Journal of cancer research and clinical oncology, 2007,133 , (11), 897-901. - 59.
Sun, C.; Wang, L.; Huang, S.; Heynen, G.J.; Prahallad, A.; Robert, C.; Haanen, J.; Blank, C.; Wesseling, J.; Willems, S.M.; Zecchin, D.; Hobor, S.; Bajpe, P.K.; Lieftink, C.; Mateus, C.; Vagner, S.; Grernrum, W.; Hofland, I.; Schlicker, A.; Wessels, L.F.; Beijersbergen, R.L.; Bardelli, A.; Di Nicolantonio, F.; Eggermont, A.M.; Bernards, R., Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature, 2014,508 , (7494), 118-122. - 60.
Motl, S., Bevacizumab in combination chemotherapy for colorectal and other cancers. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2005,62 , (10), 1021-1032. - 61.
Del Vecchio, M.; Mortarini, R.; Canova, S.; Di Guardo, L.; Pimpinelli, N.; Sertoli, M.R.; Bedognetti, D.; Queirolo, P.; Morosini, P.; Perrone, T.; Bajetta, E.; Anichini, A., Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors. Clinical cancer research : an official journal of the American Association for Cancer Research, 2010,16 , (23), 5862-5872. - 62.
Kottschade, L.A.; Suman, V.J.; Perez, D.G.; McWilliams, R.R.; Kaur, J.S.; Amatruda, T.T., 3rd; Geoffroy, F.J.; Gross, H.M.; Cohen, P.A.; Jaslowski, A.J.; Kosel, M.L.; Markovic, S.N., A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group study, N0775. Cancer, 2013,119 , (3), 586-592. - 63.
Li, B.; Lalani, A.S.; Harding, T.C.; Luan, B.; Koprivnikar, K.; Huan Tu, G.; Prell, R.; VanRoey, M.J.; Simmons, A.D.; Jooss, K., Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research, 2006,12 , (22), 6808-6816. - 64.
Mita, M.M.; Rowinsky, E.K.; Forero, L.; Eckhart, S.G.; Izbicka, E.; Weiss, G.R.; Beeram, M.; Mita, A.C.; de Bono, J.S.; Tolcher, A.W.; Hammond, L.A.; Simmons, P.; Berg, K.; Takimoto, C.; Patnaik, A., A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma. Cancer chemotherapy and pharmacology, 2007,59 , (2), 165-174. - 65.
Hasumi, Y.; Klosowska-Wardega, A.; Furuhashi, M.; Ostman, A.; Heldin, C.H.; Hellberg, C., Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling. International journal of cancer. Journal international du cancer, 2007,121 , (12), 2606-2614. - 66.
O'Reilly, T.; Lane, H.A.; Wood, J.M.; Schnell, C.; Littlewood-Evans, A.; Brueggen, J.; McSheehy, P.M., Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. Cancer chemotherapy and pharmacology, 2011,67 , (1), 193-200. - 67.
Hainsworth, J.D.; Infante, J.R.; Spigel, D.R.; Peyton, J.D.; Thompson, D.S.; Lane, C.M.; Clark, B.L.; Rubin, M.S.; Trent, D.F.; Burris, H.A., 3rd, Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: a phase 2 trial of the Sarah Cannon Oncology Research Consortium. Cancer, 2010,116 , (17), 4122-4129. - 68.
Mahalingam, D.; Malik, L.; Beeram, M.; Rodon, J.; Sankhala, K.; Mita, A.; Benjamin, D.; Ketchum, N.; Michalek, J.; Tolcher, A.; Wright, J.; Sarantopoulos, J., Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma. Cancer chemotherapy and pharmacology, 2014,74 , (1), 77-84. - 69.
Mittal, K.; Koon, H.; Elson, P.; Triozzi, P.; Dowlati, A.; Chen, H.; Borden, E.C.; Rini, B.I., Dual VEGF/VEGFR inhibition in advanced solid malignancies: Clinical effects and pharmacodynamic biomarkers. Cancer biology & therapy, 2014,15 , (8), 975-981. - 70.
Mirmohammadsadegh, A.; Mota, R.; Gustrau, A.; Hassan, M.; Nambiar, S.; Marini, A.; Bojar, H.; Tannapfel, A.; Hengge, U.R., ERK1/2 is highly phosphorylated in melanoma metastases and protects melanoma cells from cisplatin-mediated apoptosis. The Journal of investigative dermatology, 2007,127 , (9), 2207-2215. - 71.
Ivanov, V.N.; Hei, T.K., Combined treatment with EGFR inhibitors and arsenite upregulated apoptosis in human EGFR-positive melanomas: a role of suppression of the PI3K-AKT pathway. Oncogene, 2005,24 , (4), 616-626. - 72.
Sinnberg, T.; Lasithiotakis, K.; Niessner, H.; Schittek, B.; Flaherty, K.T.; Kulms, D.; Maczey, E.; Campos, M.; Gogel, J.; Garbe, C.; Meier, F., Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. The Journal of investigative dermatology, 2009,129 , (6), 1500-1515. - 73.
Keuling, A.M.; Andrew, S.E.; Tron, V.A., Inhibition of p38 MAPK enhances ABT-737-induced cell death in melanoma cell lines: novel regulation of PUMA. Pigment cell & melanoma research, 2010,23 , (3), 430-440. - 74.
Frederick, D.T.; Salas Fragomeni, R.A.; Schalck, A.; Ferreiro-Neira, I.; Hoff, T.; Cooper, Z.A.; Haq, R.; Panka, D.J.; Kwong, L.N.; Davies, M.A.; Cusack, J.C.; Flaherty, K.T.; Fisher, D.E.; Mier, J.W.; Wargo, J.A.; Sullivan, R.J., Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PloS one, 2014,9 , (7), e101286. - 75.
Ji, Z.; Kumar, R.; Taylor, M.; Rajadurai, A.; Marzuka-Alcala, A.; Chen, Y.E.; Njauw, C.N.; Flaherty, K.; Jonsson, G.; Tsao, H., Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth. Clinical cancer research : an official journal of the American Association for Cancer Research, 2013,19 , (16), 4383-4391. - 76.
Vultur, A.; Villanueva, J.; Krepler, C.; Rajan, G.; Chen, Q.; Xiao, M.; Li, L.; Gimotty, P.A.; Wilson, M.; Hayden, J.; Keeney, F.; Nathanson, K.L.; Herlyn, M., MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene, 2014,33 , (14), 1850-1861. - 77.
Martin, M.J.; Hayward, R.; Viros, A.; Marais, R., Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer discovery, 2012,2 , (4), 344-355. - 78.
Woodard, J.; Platanias, L.C., AMP-activated kinase (AMPK)-generated signals in malignant melanoma cell growth and survival. Biochemical and biophysical research communications, 2010,398 , (1), 135-139. - 79.
Niehr, F.; von Euw, E.; Attar, N.; Guo, D.; Matsunaga, D.; Sazegar, H.; Ng, C.; Glaspy, J.A.; Recio, J.A.; Lo, R.S.; Mischel, P.S.; Comin-Anduix, B.; Ribas, A., Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. Journal of translational medicine, 2011,9 , 76. - 80.
Sagoo, M.S.; Harbour, J.W.; Stebbing, J.; Bowcock, A.M., Combined PKC and MEK inhibition for treating metastatic uveal melanoma. Oncogene, 2014. - 81.
Wu, X.; Zhu, M.; Fletcher, J.A.; Giobbie-Hurder, A.; Hodi, F.S., The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma. PloS one, 2012,7 , (1), e29622. - 82.
Chen, X.; Wu, Q.; Tan, L.; Porter, D.; Jager, M.J.; Emery, C.; Bastian, B.C., Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene, 2013. - 83.
Wang, J.; Chen, J.; Miller, D.D.; Li, W., Synergistic combination of novel tubulin inhibitor ABI-274 and vemurafenib overcome vemurafenib acquired resistance in BRAFV600E melanoma. Molecular cancer therapeutics, 2014,13 , (1), 16-26. - 84.
Acquaviva, J.; Smith, D.L.; Jimenez, J.P.; Zhang, C.; Sequeira, M.; He, S.; Sang, J.; Bates, R.C.; Proia, D.A., Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Molecular cancer therapeutics, 2014,13 , (2), 353-363. - 85.
Yadav, V.; Burke, T.F.; Huber, L.; Van Horn, R.D.; Zhang, Y.; Buchanan, S.G.; Chan, E.M.; Starling, J.J.; Beckmann, R.P.; Peng, S.B., The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation. Molecular cancer therapeutics, 2014. - 86.
Hodi, F.S.; O'Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; Akerley, W.; van den Eertwegh, A.J.; Lutzky, J.; Lorigan, P.; Vaubel, J.M.; Linette, G.P.; Hogg, D.; Ottensmeier, C.H.; Lebbe, C.; Peschel, C.; Quirt, I.; Clark, J.I.; Wolchok, J.D.; Weber, J.S.; Tian, J.; Yellin, M.J.; Nichol, G.M.; Hoos, A.; Urba, W.J., Improved survival with ipilimumab in patients with metastatic melanoma. The New England journal of medicine, 2010,363 , (8), 711-723. - 87.
Srivastava, N.; McDermott, D., Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape. Cancer management and research, 2014,6 , 279-289. - 88.
Riley, J.L., Combination checkpoint blockade--taking melanoma immunotherapy to the next level. The New England journal of medicine, 2013,369 , (2), 187-189. - 89.
Maio, M.; Di Giacomo, A.M.; Robert, C.; Eggermont, A.M., Update on the role of ipilimumab in melanoma and first data on new combination therapies. Current opinion in oncology, 2013,25 , (2), 166-172. - 90.
Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; Leming, P.D.; Spigel, D.R.; Antonia, S.J.; Horn, L.; Drake, C.G.; Pardoll, D.M.; Chen, L.; Sharfman, W.H.; Anders, R.A.; Taube, J.M.; McMiller, T.L.; Xu, H.; Korman, A.J.; Jure-Kunkel, M.; Agrawal, S.; McDonald, D.; Kollia, G.D.; Gupta, A.; Wigginton, J.M.; Sznol, M., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England journal of medicine, 2012,366 , (26), 2443-2454. - 91.
Shah, D.J.; Dronca, R.S., Latest advances in chemotherapeutic, targeted, and immune approaches in the treatment of metastatic melanoma. Mayo Clinic proceedings, 2014,89 , (4), 504-519. - 92.
Perez-Gracia, J.L.; Labiano, S.; Rodriguez-Ruiz, M.E.; Sanmamed, M.F.; Melero, I., Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Current opinion in immunology, 2014,27 , 89-97. - 93.
Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; Pitot, H.C.; Hamid, O.; Bhatia, S.; Martins, R.; Eaton, K.; Chen, S.; Salay, T.M.; Alaparthy, S.; Grosso, J.F.; Korman, A.J.; Parker, S.M.; Agrawal, S.; Goldberg, S.M.; Pardoll, D.M.; Gupta, A.; Wigginton, J.M., Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. The New England journal of medicine, 2012,366 , (26), 2455-2465. - 94.
Curran, M.A.; Montalvo, W.; Yagita, H.; Allison, J.P., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences of the United States of America, 2010,107 , (9), 4275-4280. - 95.
Wolchok, J.D.; Kluger, H.; Callahan, M.K.; Postow, M.A.; Rizvi, N.A.; Lesokhin, A.M.; Segal, N.H.; Ariyan, C.E.; Gordon, R.A.; Reed, K.; Burke, M.M.; Caldwell, A.; Kronenberg, S.A.; Agunwamba, B.U.; Zhang, X.; Lowy, I.; Inzunza, H.D.; Feely, W.; Horak, C.E.; Hong, Q.; Korman, A.J.; Wigginton, J.M.; Gupta, A.; Sznol, M., Nivolumab plus ipilimumab in advanced melanoma. The New England journal of medicine, 2013,369 , (2), 122-133. - 96.
Kudchadkar, R.R.; Gibney, G.T.; Weber, J.; Chen, A.; Smith, K.; Merek, S., A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma. Journal of Clinical Oncology, 2013,31 , (15). - 97.
Hodi, F.S.; Lee, S.J.; McDermott, D.F.; Rao, U.N.M.; Butterfield, L.H.; Tarhini, A.A.; Leming, P.D.; Puzanov, I.; Kirkwood, J.M.; Grp, E.C.O., Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608. Journal of Clinical Oncology, 2013,31 , (15). - 98.
Kwong, M.L.; Neyns, B.; Yang, J.C., Adoptive T-cell transfer therapy and oncogene-targeted therapy for melanoma: the search for synergy. Clinical cancer research : an official journal of the American Association for Cancer Research, 2013,19 , (19), 5292-5299. - 99.
Wilmott, J.S.; Long, G.V.; Howle, J.R.; Haydu, L.E.; Sharma, R.N.; Thompson, J.F.; Kefford, R.F.; Hersey, P.; Scolyer, R.A., Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma. Clinical Cancer Research, 2012,18 , (5), 1386-1394. - 100.
Donia, M.; Fagone, P.; Nicoletti, F.; Andersen, R.S.; Hogdall, E.; Straten, P.T.; Andersen, M.H.; Svane, I.M., BRAF inhibition improves tumor recognition by the immune system: Potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer. Oncoimmunology, 2012,1 , (9), 1476-1483. - 101.
Liu, C.; Peng, W.; Xu, C.; Lou, Y.; Zhang, M.; Wargo, J.A.; Chen, J.Q.; Li, H.S.; Watowich, S.S.; Yang, Y.; Tompers Frederick, D.; Cooper, Z.A.; Mbofung, R.M.; Whittington, M.; Flaherty, K.T.; Woodman, S.E.; Davies, M.A.; Radvanyi, L.G.; Overwijk, W.W.; Lizee, G.; Hwu, P., BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clinical cancer research : an official journal of the American Association for Cancer Research, 2013,19 , (2), 393-403. - 102.
Jiang, X.; Zhou, J.; Giobbie-Hurder, A.; Wargo, J.; Hodi, F.S., The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research, 2013,19 , (3), 598-609. - 103.
Vella, L.J.; Pasam, A.; Dimopoulos, N.; Andrews, M.; Knights, A.; Puaux, A.L.; Louahed, J.; Chen, W.; Woods, K.; Cebon, J.S., MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. Cancer immunology research, 2014, 2, (4), 351-360. - 104.
Ribas, A.; Hodi, F.S.; Callahan, M.; Konto, C.; Wolchok, J., Hepatotoxicity with combination of vemurafenib and ipilimumab. The New England journal of medicine, 2013, 368, (14), 1365-1366.