The Role of Signaling Pathways in Melanocyte Malignant Transformation and Components of Signaling Cascades as Targets for Melanoma Therapy



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Abstract

Cutaneous melanoma, a malignant neoplasm, has shown a steady increase in incidence and high mortality in the Russian Federation and worldwide over the past decades. These factors motivate researchers and clinicians to identify new therapeutic targets with high selectivity to minimize adverse effects during antitumor therapy. The components of intracellular signaling pathways are of particular interest as potential molecular targets. This review aimed to analyze studies investigating signaling pathways in tumor cells and their role in melanocyte malignant transformation and to assess signaling cascade components as potential targets for melanoma therapy. Scientific data search was performed in the databases PubMed and RSCI. The following keywords were used: меланома (melanoma), BRAF, таргетная терапия (targeted therapy), малигнизация (malignant transformation), сигнальный путь (signaling pathway), and MAPK. Overall, 164 publications were analyzed, of which 62 were selected for inclusion in the study. The review covered studies published between 2012 and 2025. Scientific data revealed alterations in the extracellular signal-regulated kinase signaling cascade and its relationship with the protein kinase B pathway. Key driver mutations were identified, and targeted therapy strategies inhibiting various signaling pathway components were summarized. Thus, dysregulation of the extracellular signal-regulated kinase and protein kinase B signaling pathways contributes to melanoma progression, and their targeted inhibition suppresses the proliferative and metastatic activity of melanoma cells.

About the authors

Kirill P. Vorobev

Siberian State Medical University

Author for correspondence.
Email: kirill72v@gmail.com
ORCID iD: 0009-0004-9237-2086
SPIN-code: 4202-9964

Postgraduate

Russian Federation, Tomsk

Elena A. Stepovaya

Siberian State Medical University

Email: stepovaya.ea@ssmu.ru
ORCID iD: 0000-0001-9339-6304
SPIN-code: 5562-4522

MD, Dr. Sci. (Medicine), Professor, Depart. of Biochemistry and Molecular Biology with the Course of Clinical Laboratory Diagnostics

Russian Federation, Tomsk

Olga L. Nosareva

Siberian State Medical University

Email: olnosareva@yandex.ru
ORCID iD: 0000-0002-7441-5554
SPIN-code: 5688-7566

MD, Dr. Sci. (Medicine), Professor, Depart. of Biochemistry and Molecular Biology with a course in clinical laboratory diagnostics

Russian Federation, Tomsk

Ludmila V. Spirina

Siberian State Medical University

Email: spirinalvl@mail.ru
ORCID iD: 0000-0002-5269-736X
SPIN-code: 1336-8363

MD, Dr. Sci. (Medicine), Professor, Head, Depart. of Biochemistry and Molecular Biology with a course in clinical laboratory diagnostics

Russian Federation, Tomsk

Vladimir М. Nagaitsev

Siberian State Medical University

Email: vn71@list.ru
ORCID iD: 0009-0003-3921-3935

MD, Cand. Sci. (Medicine), applicant, Depart. of Biochemistry and Molecular Biology with the Course of Clinical Laboratory Diagnostics

Russian Federation, Tomsk

References

  1. Pastwińska J, Karaś K, Karwaciak I, Ratajewski M. Targeting EGFR in melanoma - The sea of possibilities to overcome drug resistance. Biochimica et Biophysica Acta (BBA). Reviews on Cancer. 2022;1877(4):188754. doi: 10.1016/j.bbcan.2022.188754 EDN: BDJIBF
  2. Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27. doi: 10.1186/1756-8722-6-27 EDN: RIGCBP
  3. Barbosa R, Acevedo LA, Marmorstein R. The MEK/ERK Network as a Therapeutic Target in Human Cancer. Mol Cancer Res. 2021;19(3):361–374. doi: 10.1158/1541-7786.MCR-20-0687 EDN: GLFLIU
  4. Timofeev O, Giron P, Lawo S, et al. ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework. NPJ Precis Oncol. 2024;8(1):70. doi: 10.1038/s41698-024-00554-5 EDN: WJIUBN
  5. Ordan M, Pallara C, Maik-Rachline G, et al. Intrinsically active MEK variants are differentially regulated by proteinases and phosphatases. Sci Rep. 2018;8(1):11830. doi: 10.1038/s41598-018-30202-5 EDN: RVELFS
  6. Cicenas J, Tamosaitis L, Kvederaviciute K, et al. KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma. Med Oncol. 2017;34(2):26. doi: 10.1007/s12032-016-0879-9 EDN: YWUAMV
  7. Mikhalenka AP, Shchayuk AN, Kilchevsky AV. Signaling pathways: a mechanism for regulating the proliferation and survival of tumor cells. Molekulyarnaya i prikladnaya genetika. 2019;26:145–157. EDN: YMEICR
  8. Mazurenko NN, Gulyaeva LF, Kushlinskii NE. The genetic markers and targets of target therapy of melanoma. Russian Clinical Laboratory Diagnostic. 2017;62(6):363–371. doi: 10.18821/0869-2084-2017-62-6-363-371 EDN: YUAQQX
  9. Noujarède J, Carrié L, Garcia V, et al. Sphingolipid paracrine signaling impairs keratinocyte adhesion to promote melanoma invasion. Cell Rep. 2023;42(12):113586. doi: 10.1016/j.celrep.2023.113586 EDN: JHIFTO
  10. Bracher A, Cardona AS, Tauber S, et al. Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. J Invest Dermatol. 2013;133(1):230–238. doi: 10.1038/jid.2012.272.
  11. Li L, Zhang S, Li H, Chou H. FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR. BMC Cancer. 2019;19(1):963. doi: 10.1186/s12885-019-6161-8 EDN: UVXRPJ
  12. Hu C, Leche CA 2nd, Kiyatkin A, et al. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature. 2022;602(7897):518–522. doi: 10.1038/s41586-021-04393-3 EDN: BWFLJB
  13. Simiczyjew A, Wądzyńska J, Kot M, et al. Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells. J Cell Mol Med. 2023;27(19):2995–3008. doi: 10.1111/jcmm.17935
  14. Billing O, Holmgren Y, Nosek D, et al. LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance. Oncogene. 2021;40(21):3707–3718. doi: 10.1038/s41388-021-01808-3 EDN: USLKGA
  15. Hoesl C, Fröhlich T, Posch C, et al. The transmembrane protein LRIG1 triggers melanocytic tumor development following chemically induced skin carcinogenesis. Mol Oncol. 2021;15(8):2140–2155. doi: 10.1002/1878-0261.12945 EDN: IHPENN
  16. Xiang S, Chen H, Luo X, et al. Isoliquiritigenin suppresses human melanoma growth by targeting miR-301b/LRIG1 signaling. J Exp Clin Cancer Res. 2018;37(1):184. doi: 10.1186/s13046-018-0844-x EDN: EWHSEJ
  17. Li W, Zhou Y. LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial-mesenchymal transition. Biosci Rep. 2019;39(1):BSR20181165. doi: 10.1042/BSR20181165
  18. Kreß JKC, Jessen C, Marquardt A, et al. NRF2 Enables EGFR Signaling in Melanoma Cells. Int J Mol Sci. 2021;22(8):3803. doi: 10.3390/ijms22083803 EDN: OHFCZR
  19. Lee KH, Suh HY, Lee MW, et al. Prognostic Significance of Epidermal Growth Factor Receptor Expression in Distant Metastatic Melanoma from Primary Cutaneous Melanoma. Ann Dermatol. 2021;33(5):432–439. doi: 10.5021/ad.2021.33.5.432 EDN: LEYYIQ
  20. Sun Y, Yu H, Zhou Y, et al. EGFR influences the resistance to targeted therapy in BRAF V600E melanomas by regulating the ferroptosis process. Arch Dermatol Res. 2025;317(1):514. doi: 10.1007/s00403-025-03895-8 EDN: OUBOGE
  21. Spada A, Gerber-Lemaire S. Surface Functionalization of Nanocarriers with Anti-EGFR Ligands for Cancer Active Targeting. Nanomaterials. 2025;15(3):158. doi: 10.3390/nano15030158 EDN: DUGXDY
  22. Muraro E, Montico B, Lum B, et al. Antibody dependent cellular cytotoxicity-inducing anti-EGFR antibodies as effective therapeutic option for cutaneous melanoma resistant to BRAF inhibitors. Front Immunol. 2024;15:1336566. doi: 10.3389/fimmu.2024.1336566 EDN: PPHXLM
  23. Rhett JM, Khan I, O'Bryan JP. Biology, pathology, and therapeutic targeting of RAS. Adv Cancer Res. 2020;148:69–146. doi: 10.1016/bs.acr.2020.05.002 EDN: TJUAAE
  24. Kolch W, Berta D, Rosta E. Dynamic regulation of RAS and RAS signaling. Biochem J. 2023;480(1):1–23. doi: 10.1042/BCJ20220234 EDN: PAWLRR
  25. Nyíri K, Koppány G, Vértessy BG. Structure-based inhibitor design of mutant RAS proteins-a paradigm shift. Cancer Metastasis Rev. 2020;39(4):1091–1105. doi: 10.1007/s10555-020-09914-6 EDN: ZRWGXP
  26. Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017;170(1):17–33. doi: 10.1016/j.cell.2017.06.009 EDN: YGGUTW
  27. Mori T, Sukeda A, Sekine S, et al. SOX10 Expression as Well as BRAF and GNAQ/11 Mutations Distinguish Pigmented Ciliary Epithelium Neoplasms From Uveal Melanomas. Invest Ophthalmol Vis Sci. 2017;58(12):5445–5451. doi: 10.1167/iovs.17-22362
  28. Burd CE, Liu W, Huynh MV, et al. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov. 2014;4(12):1418–1429. doi: 10.1158/2159-8290.CD-14-0729
  29. Jakob JA, Bassett RL Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118(16):4014–4023. doi: 10.1002/cncr.26724
  30. Cai YJ, Ke LF, Zhang WW, et al. Recurrent KRAS, KIT and SF3B1 mutations in melanoma of the female genital tract. BMC Cancer. 2021;21(1):677. doi: 10.1186/s12885-021-08427-x EDN: RXYPTL
  31. Vanni I, Tanda ET, Dalmasso B, et al. Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications. Front Mol Biosci. 2020;7:172. doi: 10.3389/fmolb.2020.00172 EDN: BLYJHS
  32. Cheng TW, Ahern MC, Giubellino A. The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification. Front Oncol. 2022;12:889223. doi: 10.3389/fonc.2022.889223 EDN: XGDRBE
  33. Deribe YL, Shi Y, Rai K, et al. Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma. Proc Natl Acad Sci U S A. 2016;113(9):E1296–E1305. doi: 10.1073/pnas.1513801113
  34. Hofmann MH, Gmachl M, Ramharter J, et al. BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition. Cancer Discov. 2021;11(1):142–157. doi: 10.1158/2159-8290.CD-20-0142 EDN: OHULTE
  35. Bery N, Legg S, Debreczeni J, et al. KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe. Nat Commun. 2019;10(1):2607. doi: 10.1038/s41467-019-10419-2 EDN: FLDJAY
  36. Quevedo CE, Cruz-Migoni A, Bery N, et al. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat Commun. 2018;9(1):3169. doi: 10.1038/s41467-018-05707-2 EDN: FVZQYI
  37. Maloney RC, Zhang M, Jang H, Nussinov R. The mechanism of activation of monomeric B-Raf V600E. Comput Struct Biotechnol J. 2021;19:3349–3363. doi: 10.1016/j.csbj.2021.06.007 EDN: BXLJRZ
  38. Maloney RC, Zhang M, Liu Y, et al. The mechanism of activation of MEK1 by B-Raf and KSR1. Cell Mol Life Sci. 2022;79(5):281. doi: 10.1007/s00018-022-04296-0 EDN: RGFZTD
  39. Cope N, Candelora C, Wong K, et al. Mechanism of BRAF Activation through Biochemical Characterization of the Recombinant Full-Length Protein. Chembiochem. 2018;19(18):1988–1997. doi: 10.1002/cbic.201800359 EDN: YKRRUD
  40. Proietti I, Skroza N, Michelini S, et al. BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions. Cancers. 2020;12(7):1823. doi: 10.3390/cancers12071823 EDN: CBKPIX
  41. Savoia P, Fava P, Casoni F, Cremona O. Targeting the ERK Signaling Pathway in Melanoma. Int J Mol Sci. 2019;20(6):1483. doi: 10.3390/ijms20061483 EDN: VXXWED
  42. Koelblinger P, Thuerigen O, Dummer R. Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018;30(2):125–133. doi: 10.1097/CCO.0000000000000426 EDN: YEQEBN
  43. Lelliott EJ, McArthur GA, Oliaro J, Sheppard KE. Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma. Front Immunol. 2021;12:661737. doi: 10.3389/fimmu.2021.661737 EDN: FCQSRN
  44. Griffin M, Scotto D, Josephs DH, et al. BRAF inhibitors: resistance and the promise of combination treatments for melanoma. Oncotarget. 2017;8(44):78174–78192. doi: 10.18632/oncotarget.19836 EDN: VREMZF
  45. Nakae S, Kitamura M, Fujiwara D, et al. Structure of mitogen-activated protein kinase kinase 1 in the DFG-out conformation. Acta Crystallogr F Struct Biol Commun. 2021;77(Pt 12):459–464. doi: 10.1107/S2053230X21011687 EDN: ITSLMT
  46. Wu PK, Park JI. MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms. Semin Oncol. 2015;42(6):849–62. doi: 10.1053/j.seminoncol.2015.09.023
  47. Kubota Y, Fujioka Y, Patil A, et al. Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer. Nat Commun. 2022;13(1):4063. doi: 10.1038/s41467-022-31690-w EDN: BVVDOE
  48. Patil K, Wang Y, Chen Z, et al. Activating mutations drive human MEK1 kinase using a gear-shifting mechanism. Biochem J. 2023;480(21):1733–1751. doi: 10.1042/BCJ20230281 EDN: XZXOQY
  49. Fleischmann J, Feichtner A, DeFalco L, et al. Allosteric Kinase Inhibitors Reshape MEK1 Kinase Activity Conformations in Cells and In Silico. Biomolecules. 2021;11(4):518. doi: 10.3390/biom11040518 EDN: WBTGOG
  50. Procaccia S, Ordan M, Cohen I, et al. Direct binding of MEK1 and MEK2 to AKT induces Foxo1 phosphorylation, cellular migration and metastasis. Sci Rep. 2017;7:43078. doi: 10.1038/srep43078 EDN: LBGQUN
  51. Algarra SM, Soriano V, Fernández-Morales L, et al. Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study. Medicine. 2017;96(52):e9523. doi: 10.1097/MD.0000000000009523 EDN: YEYALR
  52. Tran B, Cohen MS. The discovery and development of binimetinib for the treatment of melanoma. Expert Opin Drug Discov. 2020;15(7):745–754. doi: 10.1080/17460441.2020.1746265 EDN: NQVCJF
  53. Narita Y, Okamoto K, Kawada MI, et al. Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical model. Mol Cancer Ther. 2014;13(4):823–832. doi: 10.1158/1535-7163.MCT-13-0667
  54. Goetz EM, Ghandi M, Treacy DJ, et al. ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors. Cancer Res. 2014;74(23):7079–7089. doi: 10.1158/0008-5472.CAN-14-2073 EDN: UUIOJD
  55. Torres Robles J, Stiegler AL, Boggon TJ, Turk BE. Cancer hotspot mutations rewire ERK2 specificity by selective exclusion of docking interactions. J Biol Chem. 2025;301(4):108348. doi: 10.1016/j.jbc.2025.108348
  56. Leung GP, Feng T, Sigoillot FD, et al. Hyperactivation of MAPK Signaling Is Deleterious to RAS/RAF-mutant Melanoma. Mol Cancer Res. 2019;17(1):199–211. doi: 10.1158/1541-7786.MCR-18-0327 EDN: LJDHCX
  57. Johnson H, Narayan S, Sharma AK. Altering phosphorylation in cancer through PP2A modifiers. Cancer Cell Int. 2024;24(1):11. doi: 10.1186/s12935-023-03193-1 EDN: ITRRHG
  58. Arafeh R, Flores K, Keren-Paz A, et al. Combined inhibition of MEK and nuclear ERK translocation has synergistic antitumor activity in melanoma cells. Sci Rep. 2017;7(1):16345. doi: 10.1038/s41598-017-16558-0 EDN: YIAWPI
  59. Wong DJ, Robert L, Atefi MS, et al. Erratum to: Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma. Mol Cancer. 2015;14:128. doi: 10.1186/s12943-015-0393-2
  60. Qin J, Xin H, Nickoloff BJ. Specifically targeting ERK1 or ERK2 kills melanoma cells. J Transl Med. 2012;10:15. doi: 10.1186/1479-5876-10-15 EDN: VUELLO
  61. Milella M, Falcone I, Conciatori F, et al. PTEN: Multiple Functions in Human Malignant Tumors. Front Oncol. 2015;5:24. doi: 10.3389/fonc.2015.00024 EDN: UQPDSR
  62. Cao Z, Liao Q, Su M, et al. AKT and ERK dual inhibitors: The way forward? Cancer Lett. 2019;459:30–40. doi: 10.1016/j.canlet.2019.05.025 EDN: FURSPZ

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