Open access

Introductory Chapter: Melanoma and Therapeutic Perspectives

Written By

Karine Cohen Solal and Ahmed Lasfar

Submitted: January 27th, 2021 Published: May 27th, 2021

DOI: 10.5772/intechopen.97102

From the Edited Volume


Edited by Ahmed Lasfar and Karine Cohen-Solal

Chapter metrics overview

214 Chapter Downloads

View Full Metrics

1. Introduction

Malignant melanoma is one of the most aggressive forms of skin cancer, often leading to distal metastasis [1, 2]. Melanoma arises often from transformed melanocytes as a consequence of durable UV radiation. Unprecedented progress in the treatment of advanced melanoma occurred largely through advances in understanding how to target selective genetic mutations in patients with melanoma, and to unleash exiting anti-tumor immune responses [3, 4, 5]. While immunotherapy is characterized by induction of durable responses in a limited number of patients, targeted therapy has been characterized by high response rates [4, 5]. The introduction of targeted therapies has considerably improved survival rates in a significant proportion of patients with BRAF-mutant melanomas [6, 7]. However, drug resistance significantly weakens the efficacy of almost all current anticancer therapies [8, 9]. This resistance to therapy is generally driven by intrinsic or acquired tumor mechanisms [10]. Understand underlying mechanisms of resistance is crucial in elaborating novel therapeutic strategies (Figure 1).

Figure 1.

Current melanoma therapies. Several therapies are currently used in clinic for the treatment of melanoma patients. Current therapies are based on targeted therapy, immune therapy and combination therapy, consisting on association of both targeted and immune therapies. In addition, alternative therapy. Is used in many cases of drug resistance.


2. Therapeutic resistance to targeted therapy

Emergence of drug resistance, usually within several months considerably limited expected survival benefits [8, 9]. The V600E activating mutation of BRAF (MAPK pathway effector) induces constitutive activation of the kinase in 45–60% of cutaneous melanomas, and inhibitors of BRAF, MEK or both have revolutionized the treatment of patients with BRAF-mutated melanoma [10, 11]. Some mechanisms of drug resistance have been being identified and strategies to circumvent therapy failure are being investigated in preclinical models and clinical studies [12].

Accumulating evidence demonstrated that in the context of acquired resistance, tumor cells will develop mechanisms that not only promote resistance to BRAF V600E targeted therapy but also increase invasiveness favorable to further dissemination and metastasis [10, 13, 14]. The molecular effectors involved in resistance to BRAF V600E targeted therapy are simultaneously playing key roles in melanoma cell motility and invasiveness [8, 10]. Numerous studies documented that resistance is often coupled to the development of an aggressive tumor phenotype, characterized by an active epithelial-to mesenchymal (EMT)-like process, increased motility and invasion [15, 16]. As a well-documented example, transcription factors and coactivators play an active role in resistance to BRAF V600E targeted therapy, through a large variety of mechanisms [17]. In addition to promoting adaptive or acquired resistance, the expression levels of some of these transcription factors promotes a state of intrinsic resistance in the context of melanoma cells harboring BRAF V600E mutations [18, 19, 20].

General mechanisms of BRAF inhibitor resistance involve up or down regulation of transcription factors, phosphorylation of transcription factors, as well as modulation of their subcellular localization [17, 18, 19, 20]. These alterations are associated with diverse oncogenic mechanisms, such as induced expression of ERK kinases or stabilization of their phosphorylation, an increase and/or activation of specific receptor tyrosine kinases, such as EGFR, IGF-1R, AXL PDGFRβ, ERBB3, or the activation of the TGF-β signaling pathway [17, 19]. Moreover, G-protein-coupled receptors are being involved as a new protein class whose dysregulation underlies a cascade of transcriptional events resulting in resistance to BRAF inhibition. These studies altogether strongly suggest that the resistance mechanisms reestablish activation of the MAPK pathway, on which melanoma cells are highly dependent for survival, proliferation, aggressiveness and pro-metastatic behavior [17, 21]. In addition, reactivation of additional pathways, such as the PI3K/AKT pathway or GPCR-mediated cAMP/PKA/CREB pathway further operate for rewiring melanoma cells towards more aggressive characteristics in conjunction with drug resistance [21].

Simultaneous rewiring of oncogenic signaling pathways, phenotypic plasticity favoring pro-invasive behavior, actin remodeling and cytoskeletal tension, and bidirectional interplay between tumor cells and melanoma microenvironment, represent remaining challenges, for overcoming resistance to BRAF V600E inhibitors [22].

Other mechanisms of drug resistance have been identified in both melanoma patients and BRAF-animal models. Recently, it has been reported that BRAF interacts with GRP78 and removes its inhibitory impact on the three major ER stress sensors of UPR, PERK, IRE1α, and ATF6. Disconnection of GRP78 from these ER stress sensors stimulates UPR that consequently activates cytoprotective autophagy. Thus, inhibition of BRAF-induced ER stress-mediated autophagy can possibly resensitize BRAF mutant melanoma tumors to apoptosis [23].

Melanomas frequently display hyperactivity of nitric oxide synthase (NOS) and NADPH oxidase (NOX), which, respectively, produce nitric oxide (NO·) and superoxide (O2·−). The NO· and O2 react instantaneously with each other to produce peroxynitrite (ONOO) which is the driver force of melanin chemiexcitation. Melanocytes, the skin cells, specialized in synthesizing melanin, a shield against sunlight’s ultraviolet (UV) radiation. However, melanin chemiexcitation paradoxically demonstrates the melanomagenic properties of melanin. In a loop, the NOS activity regulates melanin synthesis, and melanin is utilized by the chemiexcitation pathway to generate carcinogenic melanin-carbonyls in an excited triplet state. These carbonyl compounds induce UV-specific DNA damage without UV [24].

It has been also reported that melanoma cells gain drug resistance to Temozolomide through a complex inflammatory mechanism, involving Inflammasome Sensor NLRP1 [25].

There is emergent indication that altered expression levels of microRNAs (miRNA)s induce drug-resistance in melanoma cells and that restoring adequate expression of miRNAs is critical in the re-establishment of therapeutic sensitivity [26].


3. Immunotherapy resistance

On the other hand, since the first immune checkpoint inhibitor (ICI) approval of an anti-CTL-A monoclonal antibody (mAb) in 2011 for unresectable/metastatic melanoma, the class continued to evolve, resulting in an always-changing standard of care for patients. Unfortunately, innate and acquired resistance to ICIs prevent a substantial number of patients with advanced melanoma to benefit from these clinical breakthroughs [27]. As the mechanisms responsible for both innate and acquired resistance to ICIs are further elucidated, therapeutic strategies to overcome these resistances are being clinically evaluated and will undoubtedly provide superior therapeutic efficacy [28].

As an example, clinical trials are currently evaluating inhibitors of myeloid-derived suppressors cells, which have emerged as important components in resistance to cancer immunotherapy [29, 30]. In addition, intra-tumor injection of interleukin-12, GMCSF, and Toll-like receptors (TLR9) agonists, among other agents are currently evaluated in patients with melanoma refractory to anti-PD1 blockade [31, 32]. Another approach clinically tested in patients with BRAFV600E is the triple combination of an approved anti-PD-L1 monoclonal antibody and an approved combination of BRAF inhibitor/MEK inhibitor; this triplet regimen is based on the rationale that BRAF inhibition increases the penetration of T cells into the tumors, a major factor in the ability to respond to ICIs [33]. Altogether, the different approaches aim at transforming a cold tumor, characterized by a lack or paucity of tumor T cell infiltration, into a hot, inflamed tumor.


4. Alternative therapeutic strategies

Other alternative approaches have been elaborated in the treatment of metastatic melanoma such as Photodynamic therapy (PDT), which relies on a light-activated compound to produce death-inducing amounts of reactive oxygen species (ROS) [34].

Histone Deacetylase Inhibitors have been also developed to overcome resistance to targeted and immunotherapy in Metastatic Melanoma [35].

Nanotechnology, based therapy or neoadjuvant therapy represent an active area of investigation as demonstrated by several clinical trials [36]. These novel strategies may offer a multitude of benefits which could improve the survival outcomes of melanoma patients, with low adverse effects. Their combination with immunotherapies and vaccines are expected to overcome drug resistance, offering survival benefits to a greater population of patients with advanced melanoma, while maintaining a satisfying quality of life.


5. Conclusion

The future of patients with unresectable and advanced melanoma is looking brighter than a decade ago. Besides immunotherapy revolution, promising approaches are emerging. Currently combination therapy, based on targeted therapy and immune checkpoint inhibitors is commonly recommended for increasing treatment efficacy. However, many challenges remain, regarding the mechanisms of tumorigenesis, the impact of tumor microenvironment on the immunogenicity of melanoma.


  1. 1. Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7-30
  2. 2. Leonardi GC, Falzone L, Salemi R, Zanghì A, Spandidos DA, McCubrey JA, Candido S and Libra M: Cutaneous melanoma: From pathogenesis to therapy (Review). Int J Oncol. 52:1071-1080. 2018
  3. 3. Jenkins RW, Fisher DE. Treatment of Advanced Melanoma in 2020 and Beyond. J Invest Dermatol. 2021 Jan;141(1):23-31. doi: 10.1016/j.jid.2020.03.943. Epub 2020 Apr 5. PMID: 32268150; PMCID: PMC7541692
  4. 4. Massimo Ralli, Andrea Botticelli, Irene Claudia Visconti, Diletta Angeletti, Marco Fiore, Paolo Marchetti, Alessandro Lambiase, Marco de Vincentiis, Antonio Greco, “Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions”, Journal of Immunology Research, vol. 2020, Article ID 9235638, 12 pages, 2020
  5. 5. Leonardi GC, Candido S, Falzone L, Spandidos DA, Libra M. Cutaneous melanoma and the immunotherapy revolution (Review). Int J Oncol. 2020 Sep;57(3):609-618. doi: 10.3892/ijo.2020.5088. Epub 2020 Jun 25. PMID: 32582963; PMCID: PMC7384846
  6. 6. Falcone I, Conciatori F, Bazzichetto C, Ferretti G, Cognetti F, Ciuffreda L, Milella M. Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy. Cancers (Basel). 2020 Oct 6;12(10):2870. doi: 10.3390/cancers12102870. PMID: 33036192; PMCID: PMC7601592
  7. 7. Liguoro D, Fattore L, Mancini R, Ciliberto G. Drug tolerance to target therapy in melanoma revealed at single cell level: What next? Biochim Biophys Acta Rev Cancer. 2020 Dec;1874(2):188440. doi: 10.1016/j.bbcan.2020.188440. Epub 2020 Sep 29. PMID:33007433
  8. 8. Tangella LP, Clark ME, Gray ES. Resistance mechanisms to targeted therapy in BRAF-mutant melanoma - A mini review. Biochim Biophys Acta Gen Subj. 2021 Jan;1865(1):129736. doi: 10.1016/j.bbagen.2020.129736. Epub 2020 Sep 18. PMID:32956754
  9. 9. Mazurkiewicz J, Simiczyjew A, Dratkiewicz E, Ziętek M, Matkowski R, Nowak D. Stromal Cells Present in the Melanoma Niche Affect Tumor Invasiveness and Its Resistance to Therapy. Int J Mol Sci. 2021 Jan 7;22(2):529. doi: 10.3390/ijms22020529. PMID: 33430277; PMCID: PMC7825728
  10. 10. Kakadia S, Yarlagadda N, Awad R, Kundranda M, Niu J, Naraev B, Mina L, Dragovich T, Gimbel M, Mahmoud F. Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma. Onco Targets Ther. 2018 Oct 17;11:7095-7107. doi: 10.2147/OTT.S182721. PMID: 30410366; PMCID: PMC6200076
  11. 11. Alqathama A. BRAF in malignant melanoma progression and metastasis: potentials and challenges. Am J Cancer Res. 2020 Apr 1;10(4):1103-1114. PMID: 32368388; PMCID: PMC7191094
  12. 12. Tanda ET, Vanni I, Boutros A, Andreotti V, Bruno W, Ghiorzo P, Spagnolo F. Current State of Target Treatment in BRAF Mutated Melanoma. Front Mol Biosci. 2020 Jul 14;7:154. doi: 10.3389/fmolb.2020.00154. PMID: 32760738; PMCID: PMC7371970
  13. 13. Ray A, Kunhiraman H, Perera RJ. The Paradoxical Behavior of microRNA-211 in Melanomas and Other Human Cancers. Front Oncol. 2021 Feb 8;10:628367. doi: 10.3389/fonc.2020.628367. PMID: 33628737; PMCID: PMC7897698
  14. 14. Patton EE, Mueller KL, Adams DJ, Anandasabapathy N, Aplin AE, Bertolotto C, Bosenberg M, Ceol CJ, Burd CE, Chi P, Herlyn M, Holmen SL, Karreth FA, Kaufman CK, Khan S, Kobold S, Leucci E, Levy C, Lombard DB, Lund AW, Marie KL, Marine JC, Marais R, McMahon M, Robles-Espinoza CD, Ronai ZA, Samuels Y, Soengas MS, Villanueva J, Weeraratna AT, White RM, Yeh I, Zhu J, Zon LI, Hurlbert MS, Merlino G. Melanoma models for the next generation of therapies. Cancer Cell. 2021 Feb 4:S1535-6108(21)00055-6. doi: 10.1016/j.ccell.2021.01.011. Epub ahead of print. PMID:33545064
  15. 15. Tang Y, Durand S, Dalle S, Caramel J. EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment. Cancers (Basel). 2020 Aug 4;12(8):2154. doi: 10.3390/cancers12082154. PMID: 32759677; PMCID: PMC7465730
  16. 16. Hodorogea A, Calinescu A, Antohe M, Balaban M, Nedelcu RI, Turcu G, Ion DA, Badarau IA, Popescu CM, Popescu R, Popp C, Cioplea M, Nichita L, Hulea I, Brinzea A. Epithelial-Mesenchymal Transition in Skin Cancers: A Review. Anal Cell Pathol (Amst). 2019 Dec 16;2019:3851576. doi: 10.1155/2019/3851576. PMID: 31934531; PMCID: PMC6942705
  17. 17. Cohen-Solal KA, Kaufman HL, Lasfar A. Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development. Pigment Cell Melanoma Res. 2018 Mar;31(2):241-252. doi: 10.1111/pcmr.12666. Epub 2017 Nov 15. PMID:29090514
  18. 18. Hüser L, Kokkaleniou MM, Granados K, Dworacek J, Federico A, Vierthaler M, Novak D, Arkhypov I, Hielscher T, Umansky V, Altevogt P, Utikal J. HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma. Cancers (Basel). 2020 Dec 14;12(12):3761. doi: 10.3390/cancers12123761. PMID: 33327495; PMCID: PMC7764938
  19. 19. Azimi A, Tuominen R, Costa Svedman F, Caramuta S, Pernemalm M, Frostvik Stolt M, Kanter L, Kharaziha P, Lehtiö J, Hertzman Johansson C, Höiom V, Hansson J, Egyhazi Brage S. Silencing FLI or targeting CD13/ANPEP lead to dephosphorylation of EPHA2, a mediator of BRAF inhibitor resistance, and induce growth arrest or apoptosis in melanoma cells. Cell Death Dis. 2017 Aug 31;8(8):e3029. doi: 10.1038/cddis.2017.406. PMID: 29048432; PMCID: PMC5596587
  20. 20. Liu L, Yue Q , Ma J, Liu Y, Zhao T, Guo W, Zhu G, Guo S, Wang S, Gao T, Li C, Shi Q . POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation. Cell Death Dis. 2020 Jun 12;11(6):451. doi: 10.1038/s41419-020-2662-2. PMID: 32532957; PMCID: PMC7293281
  21. 21. Eddy K, Shah R, Chen S. Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities. Front Oncol. 2021 Feb 4;10:626129. doi: 10.3389/fonc.2020.626129. PMID: 33614507; PMCID: PMC7891057
  22. 22. Dumaz N, Lebbé C. New perspectives on targeting RAF, MEK and ERK in melanoma. Curr Opin Oncol. 2021 Mar 1;33(2):120-126. doi: 10.1097/CCO.0000000000000708. PMID:33332926
  23. 23. Rather RA, Bhagat M, Singh SK. Oncogenic BRAF, endoplasmic reticulum stress, and autophagy: Crosstalk and therapeutic targets in cutaneous melanoma. Mutat Res. 2020 Jul-Sep;785:108321. doi: 10.1016/j.mrrev.2020.108321. Epub 2020 Jul 7. PMID: 32800272)
  24. 24. Premi S. Role of Melanin Chemiexcitation in Melanoma Progression and Drug Resistance. Front Oncol. 2020 Aug 6;10:1305. doi: 10.3389/fonc.2020.01305. PMID: 32850409; PMCID: PMC7425655
  25. 25. Zhai Z, Samson JM, Yamauchi T, Vaddi PK, Matsumoto Y, Dinarello CA, Ravindran Menon D, Fujita M. Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma. Cancers (Basel). 2020 Sep 4;12(9):2518. doi: 10.3390/cancers12092518. PMID: 32899791; PMCID: PMC7563249
  26. 26. Motti ML, Minopoli M, Di Carluccio G, Ascierto PA, Carriero MV. MicroRNAs as Key Players in Melanoma Cell Resistance to MAPK and Immune Checkpoint Inhibitors. Int J Mol Sci. 2020 Jun 26;21(12):4544. doi: 10.3390/ijms21124544. PMID: 32604720; PMCID: PMC7352536
  27. 27. Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol. 2021 Jan 24;16:223-249. doi: 10.1146/annurev-pathol-042020-042741. Epub 2020 Nov 16. PMID:33197221
  28. 28. Bai X, Flaherty KT. Targeted and immunotherapies in BRAF mutant melanoma: where we stand and what to expect. Br J Dermatol. 2020 Jul 11. doi: 10.1111/bjd.19394. Epub ahead of print. PMID:32652567
  29. 29. Chevolet I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C, Van Gele M, van Geel N, Brochez L. Clinical significance of plasmacytoid dendritic cells and myeloid-derived suppressor cells in melanoma. J Transl Med. 2015 Jan 16;13:9. doi: 10.1186/s12967-014-0376-x. PMID: 25592374; PMCID: PMC4326397
  30. 30. Groth C, Arpinati L, Shaul ME, Winkler N, Diester K, Gengenbacher N, Weber R, Arkhypov I, Lasser S, Petrova V, Augustin HG, Altevogt P, Utikal J, Fridlender ZG, Umansky V. Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression. Cancers (Basel). 2021 Feb 10;13(4):726. doi: 10.3390/cancers13040726. PMID:33578808
  31. 31. Kim KJ, Moon D, Kong SJ, Lee YS, Yoo Y, Kim S, Kim C, Chon HJ, Kim JH, Choi KJ. Antitumor effects of IL-12 and GM-CSF co-expressed in an engineered oncolytic HSV-1. Gene Ther. 2020 Nov 4. doi: 10.1038/s41434-020-00205-x. Epub ahead of print. PMID:33149278
  32. 32. Levy ES, Chang R, Zamecnik CR, Dhariwala MO, Fong L, Desai TA. Multi-Immune Agonist Nanoparticle Therapy Stimulates Type I Interferons to Activate Antigen-Presenting Cells and Induce Antigen-Specific Antitumor Immunity. Mol Pharm. 2021 Feb 4. doi: 10.1021/acs.molpharmaceut.0c00984. Epub ahead of print. PMID:33541072
  33. 33. Cooper ZA, Reuben A, Austin-Breneman J, Wargo JA. Does It MEK a Difference? Understanding Immune Effects of Targeted Therapy. Clin Cancer Res. 2015 Jul 15;21(14):3102-4. doi: 10.1158/1078-0432.CCR-15-0363. Epub 2015 May 29. PMID: 26025561; PMCID: PMC4506225
  34. 34. Biteghe FAN, Chalomie NET, Mungra N, Vignaux G, Gao N, Vergeade A, Okem A, Naran K, Ndong JC, Barth S. Antibody-Based Immunotherapy: Alternative Approaches for the Treatment of Metastatic Melanoma. Biomedicines. 2020 Sep 3;8(9):327. doi: 10.3390/biomedicines8090327. PMID: 32899183; PMCID: PMC7555584
  35. 35. Yeon M, Kim Y, Jung HS, Jeoung D. Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma. Front Cell Dev Biol. 2020 Jun 17;8:486. doi: 10.3389/fcell.2020.00486. PMID: 32626712; PMCID: PMC7311641
  36. 36. Kelly ZR, Gorantla VC, Davar D. The Role of Neoadjuvant Therapy in Melanoma. Curr Oncol Rep. 2020 Jun 29;22(8):80. doi: 10.1007/s11912-020-00944-5. PMID:32601947

Written By

Karine Cohen Solal and Ahmed Lasfar

Submitted: January 27th, 2021 Published: May 27th, 2021