open access

Vol 4, No 3 (2019)
REVIEW ARTICLES
Published online: 2019-09-26
Get Citation

Signaling pathways in melanoma biology and new targeted therapeutic approaches

Aleksander Kiełbik, Piotr Wawryka, Agnieszka Chwiłkowska, Jolanta Saczko, Julita Kulbacka
DOI: 10.5603/MRJ.a2019.0033
·
Medical Research Journal 2019;4(3):184-188.

open access

Vol 4, No 3 (2019)
REVIEW ARTICLES
Published online: 2019-09-26

Abstract

Despite the broad prevention programs and early detection and therapy progress, melanoma of skin is still responsible for 0.6% of deaths caused by tumour disease. Every year 300,000 patients are diagnosed and 60,000 die from the most malignant of skin cancer. Generally, melanoma is formed as a result of mutation of growth pathways responsible for proliferation and apoptosis. One of the most investigated pathway, mutated in 90% of melanomas, is RAS > RAF > MEK > ERK also known as mitogen-activated protein kinase (MAPK) pathway. The second one is phosphoinositide-3-OH kinase (PI3K) pathway. The better understanding of melanoma biology resulted in research of inhibitors, which can affect presented pathways and prevent uncontrolled proliferation of melanoma. The BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib seem to be the most successful ones. Recent advances in biology of melanoma provided new interesting therapeutic targets. One of the most inquiring is microphthalmia associated transcription factor (MITF), the principal regulator of melanocyte lineage. MITF perform the role of so-called ‘survival’ or ‘addiction’ oncogene. Moreover, the interleukin-1 receptor-associated kinases (IRAKs) might clarify the connection between the inflammatory environment and melanoma carcinogenesis. IRAKs play a key role as mediators of toll-like receptor (TLR) and interleukin-1 receptor (IL1R) in inflammation signalling processes. Moreover, it was observed that metformin cause cell cycle arrest in melanoma cells, secondly leading to activation of autophagy and apoptosis. Although due to targeted and immunotherapy the prognosis of patients with metastatic melanoma is incomparably better, melanoma in its advanced stadium is still predominantly lethal. Therefore, the most present research concentrates on acquired resistance against targeted therapy.

Abstract

Despite the broad prevention programs and early detection and therapy progress, melanoma of skin is still responsible for 0.6% of deaths caused by tumour disease. Every year 300,000 patients are diagnosed and 60,000 die from the most malignant of skin cancer. Generally, melanoma is formed as a result of mutation of growth pathways responsible for proliferation and apoptosis. One of the most investigated pathway, mutated in 90% of melanomas, is RAS > RAF > MEK > ERK also known as mitogen-activated protein kinase (MAPK) pathway. The second one is phosphoinositide-3-OH kinase (PI3K) pathway. The better understanding of melanoma biology resulted in research of inhibitors, which can affect presented pathways and prevent uncontrolled proliferation of melanoma. The BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib seem to be the most successful ones. Recent advances in biology of melanoma provided new interesting therapeutic targets. One of the most inquiring is microphthalmia associated transcription factor (MITF), the principal regulator of melanocyte lineage. MITF perform the role of so-called ‘survival’ or ‘addiction’ oncogene. Moreover, the interleukin-1 receptor-associated kinases (IRAKs) might clarify the connection between the inflammatory environment and melanoma carcinogenesis. IRAKs play a key role as mediators of toll-like receptor (TLR) and interleukin-1 receptor (IL1R) in inflammation signalling processes. Moreover, it was observed that metformin cause cell cycle arrest in melanoma cells, secondly leading to activation of autophagy and apoptosis. Although due to targeted and immunotherapy the prognosis of patients with metastatic melanoma is incomparably better, melanoma in its advanced stadium is still predominantly lethal. Therefore, the most present research concentrates on acquired resistance against targeted therapy.

Get Citation

Keywords

melanoma, targeted therapy, dermatology, oncology

About this article
Title

Signaling pathways in melanoma biology and new targeted therapeutic approaches

Journal

Medical Research Journal

Issue

Vol 4, No 3 (2019)

Pages

184-188

Published online

2019-09-26

DOI

10.5603/MRJ.a2019.0033

Bibliographic record

Medical Research Journal 2019;4(3):184-188.

Keywords

melanoma
targeted therapy
dermatology
oncology

Authors

Aleksander Kiełbik
Piotr Wawryka
Agnieszka Chwiłkowska
Jolanta Saczko
Julita Kulbacka

References (41)
  1. Cichorek M, Wachulska M, Stasiewicz A, et al. Skin melanocytes: biology and development. Postepy Dermatol Alergol. 2013; 30(1): 30–41.
  2. Clark WH, Elder DE, Guerry D, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst. 1989; 81(24): 1893–1904.
  3. Scolyer RA, Long GV, Thompson JF. Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. Mol Oncol. 2011; 5(2): 124–136.
  4. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394–424.
  5. Cummins DL, Cummins JM, Pantle H, et al. Cutaneous malignant melanoma. Mayo Clin Proc. 2006; 81(4): 500–507.
  6. Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev. 2005; 14(3): 562–566.
  7. Wellbrock C, Arozarena I. The Complexity of the ERK/MAP-Kinase Pathway and the Treatment of Melanoma Skin Cancer. Front Cell Dev Biol. 2016; 4: 33.
  8. Kwong LN, Costello JC, Liu H, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012; 18(10): 1503–1510.
  9. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892): 949–954.
  10. Sharma A, Trivedi NR, Zimmerman MA, et al. Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res. 2005; 65(6): 2412–2421.
  11. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003; 22(20): 3113–3122.
  12. Tsao H, Goel V, Wu H, et al. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J Invest Dermatol. 2004; 122(2): 337–341.
  13. Rodriguez-Viciana P, Marte BM, Warne PH, et al. Phosphatidylinositol 3' kinase: one of the effectors of Ras. Philos Trans R Soc Lond B Biol Sci. 1996; 351(1336): 225–31; discussion 231.
  14. Papp T, Pemsel H, Rollwitz I, et al. Mutational analysis of N-ras, p53, CDKN2A (p16(INK4a)), p14(ARF), CDK4, and MC1R genes in human dysplastic melanocytic naevi. J Med Genet. 2003; 40(2): E14.
  15. Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007; 445(7130): 851–857.
  16. Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005; 436(7047): 117–122.
  17. Levy C, Khaled M, Fisher DE. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med. 2006; 12(9): 406–414.
  18. Zuo L, Weger J, Yang Q, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996; 12(1): 97–99.
  19. Bennett DC. Human melanocyte senescence and melanoma susceptibility genes. Oncogene. 2003; 22(20): 3063–3069.
  20. Alcorta DA, Xiong Y, Phelps D, et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A. 1996; 93(24): 13742–13747.
  21. Rhyasen GW, Starczynowski DT. IRAK signalling in cancer. Br J Cancer. 2015; 112(2): 232–237.
  22. Lin KM, Hu W, Troutman TyD, et al. IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. Proc Natl Acad Sci U S A. 2014; 111(2): 775–780.
  23. Srivastava R, Geng D, Liu Y, et al. Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4. Cancer Res. 2012; 72(23): 6209–6216.
  24. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010; 467(7315): 596–599.
  25. Hauschild A, Grob JJ, Demidov L, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet. 2012; 380(9839): 358–365.
  26. Gilmartin AG, Bleam MR, Groy A, et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin Cancer Res. 2011; 17(5): 989–1000.
  27. Chapman PB, Hauschild A, Robert C, et al. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364(26): 2507–2516.
  28. Flaherty KT, Robert C, Hersey P, et al. METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367(2): 107–114.
  29. Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014; 4(1): 80–93.
  30. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015; 372(1): 30–39.
  31. Long GV, Eroglu Z, Infante J, et al. Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. J Clin Oncol. 2018; 36(7): 667–673.
  32. Long G, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The Lancet. 2015; 386(9992): 444–451.
  33. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8): 1167–1174.
  34. Jaune E, Rocchi S. Metformin: Focus on Melanoma. Frontiers in Endocrinology. 2018; 9.
  35. Tomic T, Botton T, Cerezo M, et al. Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis. 2011; 2: e199.
  36. Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A. 2013; 110(3): 972–977.
  37. Liu X, Romero IL, Litchfield LM, et al. Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers. Cell Metab. 2016; 24(5): 728–739.
  38. Niehr F, von Euw E, Attar N, et al. Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med. 2011; 9: 76.
  39. Dummer R, Ascierto P, Gogas H, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. 2018; 19(10): 1315–1327.
  40. Ascierto P, McArthur G, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet Oncology. 2016; 17(9): 1248–1260.
  41. Maio M, Lewis K, Demidov L, et al. Adjuvant vemurafenib in resected, BRAF V600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. The Lancet Oncology. 2018; 19(4): 510–520.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.