Molecular Targets in Melanoma
Melanoma is one of the most deadly forms of skin cancer. The incidence of melanoma has been steadily increasing over the last several decades. It is estimated that in 2010 68,130 adults were diagnosed with melanoma, and 8,700 patients died of this disease (Jemal et al.). Melanoma is highly curable when it is diagnosed at early stages. However, patients with distant metastases have a median overall survival of only 6-8 months (Balch et al. 2009). Chemotherapy regimens have not improved survival in patients with metastatic melanoma, and immunotherapies have generally benefited only a small percentage of patients (Koon and Atkins 2006). Thus, there is a critical need to develop more effective therapeutic approaches for this disease. Recently, dramatic results have been reported with agents that specifically target proteins or pathways that are aberrant in this disease, such as
2. Melanoma molecular targets
Melanoma has traditionally been classified based on the clinical and pathological features of the tumor. The most commonly observed type of melanoma is cutaneous melanoma (CM), arising from skin with either intermittent or chronic sun exposure. While ultraviolet radiation likely has a significant causative role in these tumors, its role in certain other subtypes is less clear. Cutaneous melanomas can arise in areas with limited sun/UV radiation exposure such as palms, soles and the area under nails (acral lentiginous melanoma). Other melanomas arise from mucosal surfaces of the body, including the upper aerodigestive, gastrointestinal, and genitourinary tracts, and are termed mucosal melanomas. Melanomas also originate from melanocytes in the uveal tract of the eye (uveal/ocular melanoma). In addition to anatomic differences, recent research has demonstrated that the different melanoma subtypes are characterized by distinct regions of DNA copy number gain and loss (Curtin et al. 2005). This finding suggested that each of these tumor types could be characterized by distinct molecular mechanisms, a hypothesis that is also supported by the marked variance of recently described oncogenic mutations across the different melanoma subtypes.
2.1. RAS/RAF/MAPK pathway
The RAS/RAF/MAPK cascade is a critical growth and survival signaling pathway in cells. The pathway is generally triggered by activation of cell surface receptor(s) [i.e., receptor tyrosine kinases (RTK), G-protein coupled receptors (GPCR), etc] following ligand binding or cell-to-cell contact. The receptors induce activation of RAS through guanine exchange factors (GEFs), which promote the exchange of RAS-GDP to RAS-GTP. GTP-bound RAS recruits and activates the RAF (A-, B- and C-RAF) family of serine-threonine kinases, which then phosphorylate and activate Mitogen Activated Kinase Kinase [MAPKK or MAP/ERK kinase (MEK)]. Phosphorylated MEK, which is also a kinase, activates the downstream Extracellular Regulatory Kinase (ERK1/2 or P44/42 MAPK) through phosphorylation. Once activated, ERK translocates to the nucleus where it regulates the expression of several genes involved in differentiation, survival and proliferation by phosphorylating transcription factors such as ETS, MYC etc. The MAPK pathway also regulates the apoptotic machinery in cells through post-translational regulation of BAD, BIM, MCL-1 and BCL-2 proteins (George, Thomas, and Hannan).
In addition to RAF, the RAS proteins activate several other effectors that contribute to the pro-survival and proliferative phenotype, including phospholipase C (PLC), phosphatidyl inositol-3-Kinase (PI3K), Ral, Rac and Rho-GTPases. Mutations in the
Activating mutations in the serine/threonine kinase
In melanoma, activating
The dual specificity kinases MEK1/2 that lie downstream of BRAF are activated in majority of the cancers with deregulated RAS/RAF/MAPK signaling. The MEK kinases phosphorylate ERK1/2 downstream and mediate cell survival signaling through MAPK signaling cascade. Emery et al. (2009), using random mutagenesis and massive parallel sequencing approaches identified mutations in the drug binding and regulatory domains of MEK1 kinase that led to increased phosphorylation of ERK and a MEK inhibitor-resistance phenotype. Subsequently
2.2. PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is one of the most important intracellular signaling pathways. The pathway regulates many important cellular processes, including proliferation, differentiation, motility, metabolism, survival, invasion and intracellular transport (Engelman, Luo, and Cantley 2006). The Phosphatidyl Inositol-3 Kinases (PI3K) are a family of lipid kinases that are composed of an adaptor/regulatory subunit (i.e. p85) and a catalytic unit (i.e. p110). Similar to RAS/RAF/ERK, the PI3K/AKT/mTOR pathway is activated by a variety of signals, including receptor tyrosine kinases and RAS proteins. Activation of PI3K results in phosphorylation of phosphatidylinositols in the cell membrane at the 3’-hydroxyl group. This reaction generates the lipid species PI (3,4)P2 and PI(3,4,5)P3. PI (3,4)P2 and PI(3,4,5)P3 act as second messengers, recruiting proteins that contain a pleckstrin homology (PH) domain to the cell membrane, such as the serine/threonine kinases AKT and PDK1. Upon recruitment to the cell membrane, AKT is phosphorylated at two critical residues, serine 473 and threonine 308. Once phosphorylated, the activated AKT translocates to the cytosol where it promotes cell proliferation and survival by phosphorylating numerous substrate proteins including mTOR, GSK3, FOXO, and BAD, among others.
The activity of the PI3K/AKT/mTOR pathway is normally controlled by the lipid phosphatase PTEN (Phosphatase and Tensin Homolog), which dephosphorylates phosphatidyl inositols (PI) at the 3’ position, thereby inhibiting PI3K-mediated signaling (Maehama and Dixon 1998). PTEN, which is a tumor suppressor, is inactivated in a variety of tumor types, through both genetic and epigenetic mechanisms (Li et al. 1997; Myers et al. 1998; Mirmohammadsadegh et al. 2006). Tumors with loss of PTEN are characterized by markedly increased basal activation of AKT (Davies et al. 1999; Davies et al. 1998; Davies et al. 2009).
In addition to loss of PTEN, the PI3K/AKT/mTOR pathway may also be activated by gene amplifications and gain of function mutations in other pathway components. Rare activating mutations in
2.3. Receptor tyrosine kinases
Activating mutations or amplifications of receptor tyrosine kinases are implicated in multiple tumor types, including gastrointestinal stromal tumors (GIST) (
More recently, high-throughput sequencing analysis of all protein kinases identified novel somatic mutations in 19 different genes (Prickett et al. 2009). The most frequently mutated gene was
2.4. G proteins
Heterotrimeric guanine nucleotide-binding proteins (G proteins) are a diverse family of proteins that regulate and propagate signals from G-Protein Coupled Receptors (GPCRs) that are expressed at the cell membrane. The complex of G-proteins and GPCRs activate several key signaling pathways involved in cell survival, proliferation, and transformation. There is growing evidence that this family of genes may play a significant role in certain subtypes of melanoma.
A role for G proteins in melanoma was first suggested by a preclinical study that was designed to identify genes that promote melanin synthesis and pigmentation in mice. Two different G protein alpha subunits,
Over 90% of the reported mutations in
In addition to these mutations in uveal melanoma, high-throughput sequencing for mutations in G protein family members in cutaneous melanomas identified 18 non-synonymous somatic mutations in G protein subunits spanning seven genes (Cardenas-Navia et al.). Mutations were identified in
2.5. Other affected genes
Alterations in several regulators of cell cycle progression have also been implicated in melanoma. Allelic alterations in
A comparative genetic analysis of melanomas with other tumor types identified selective amplifications of the gene encoding the microphthalmia-associated transcription factor (
3. Clinical targeting of activated pathways in melanoma
The treatment of many cancers has changed dramatically due to an improved understanding of the genes and pathways that contribute to the aggressive nature of many of these diseases. The discovery of activating events in kinase signaling pathways in melanoma rapidly led to clinical testing of a number of targeted therapies for this disease. The early results illustrate both the promise and challenge of this strategy.
3.1. The RAS/RAF/MAPK pathway
The high prevalence of mutations in components of the RAS/RAF/MAPK pathway in melanoma, particularly in the most common subtype (cutaneous), strongly supports the rationale to test the clinical efficacy of drugs against it. After the discovery of activating
The identification of mutant
While the high response rate with minimal toxicity with PLX4032 and GSK2118436 is unprecedented, it is now becoming clear that resistance will be a major problem with these agents. In the phase I trial of PLX4032, virtually all patients who responded clinically went on to develop disease progression, with a median duration of response of approximately 7 months (Flaherty et al. 2010). While the experience with resistance to targeted therapies in other diseases made it reasonable to hypothesize that secondary
In addition to BRAF inhibitors, MEK inhibitors have shown promise in the treatment of metastatic melanoma. The initial presentation of the preliminary results of the phase I trial of GSK1120212, an orally available MEK inhibitor with a very long half life, reported a 40% ORR response among patients with metastatic melanoma (Infante et al. 2010). This response rate is higher than previous reports with other MEK inhibitors, such as AZD6244 (Dummer et al. 2008). Preclinical studies demonstrated that, similar to the results with BRAF inhibitors, loss of PTEN correlates with increased resistance to cell killing by MEK inhibitors (Gopal et al. 2010). Interestingly, several cells with normal PTEN expression but similar resistance developed activation of the PI3K-AKT pathway following treatment with MEK inhibitors. This compensatory mechanism, which was mediated by the insulin-like growth factor-1 receptor, gives further support to the rationale for testing the effects of targeted therapy combinations to improve clinical results with both BRAF and MEK inhibitors.
Imatinib, a small molecule inhibitor of a number of kinases, is approved by the FDA for the first-line treatment of metastatic GISTs, which are characterized by a high (~80%) prevalence of activating mutations in the
There are now several case reports describing impressive clinical responses to c-KIT inhibitors in melanoma patients with mutations in the
||Cutaneous "/"/ Acral "/ Mucosal||Selective BRAF inhibitors
Non-Selective BRAF Inhibitors
||Cutaneous "/ Acral "/ Mucosal||Farnesyl transferase inhibitors|
Dual PI3K/mTOR inhibitors
||Mucosal "/ Acral "/"/ Cutaneous||c-KIT inhibitors|
The testing and treatment of melanoma patients is evolving rapidly due to an improved understanding of the genes and pathways that are genetically altered in this disease. The dramatic responses of melanoma patients with
There is a clear need to improve our understanding of the factors that are present at baseline that allow resistance to occur to BRAF and c-KIT inhibitors, as well as changes that evolve over time to manifest the resistance. An improved understanding of pre-treatment factors that facilitate the eventual emergence of resistance may suggest rational combinatorial approaches that can prevent resistance from developing. Such factors may also serve as markers that clinically distinguish patients who need combinatorial treatments, which are likely to incur additional toxicities, from those who may achieve significant benefit from single-agent therapy. Similarly, determining the changes that evolve over time and correlate with functional resistance will also suggest rational combinatorial approaches that can be used after single-agent therapies fail. While it is reasonable to hypothesize that many of the critical mechanisms that underlie resistance will involve changes in signaling pathways in the tumors, the possibility of other factors should not be dismissed. For example, recent research has demonstrated that targeted therapies against the RAS/RAF/MAPK pathway can influence both the ability of immune cells to recognize melanomas, and their proliferation and survival (Boni et al. 2010). As immunotherapies have been associated with relatively low response rates but durable benefit when they occur, it is possible that strategies that combine such approaches with targeted therapies may have synergistic clinical benefit.
While there are now clearly defined challenges for patients with
Overall, recent discoveries have provided new hope and therapeutic options for patients with melanoma. These advances highlight the potential of translational research, and provide the impetus for continued research of this highly aggressive disease.
M.A.D. reports receiving research funding from AstraZeneca, GlaxoSmithKline, and Merck. M.A.D. is supported by a Career Development Award from the American Society of Clinical Oncology, a Young Investigator Award from the Melanoma Research Alliance, and is the Goodfellow Scholar of the MD Anderson Cancer Center Physician Scientist Program.
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