ГЕНЕТИЧЕСКИЕ МАРКЕРЫ И МИШЕНИ ТАРГЕТНОЙ ТЕРАПИИ МЕЛАНОМЫ

Аннотация

Меланома — наиболее опасное злокачественное заболевание кожи с высоким риском рецидивирования и метастазирования. Молекулярно-биологические исследования, выполненные в последнее десятилетие, кардинально изменили наши представления о механизмах канцерогенеза меланоцитов. В обзоре рассматриваются как наследственные факторы предрасположенности к меланоме (редкие аллели генов CDKN2A и CDK4, мутации MITF и BAP1), так и соматические генетические нарушения, вовлеченные в канцерогенез меланомы. Это мутации в генах, вызывающих гиперактивацию RAS-MAPK (BRAF, NRAS, MEK, NF1) и PI3K- (PTEN, AKT) сигнальных путей, а также генов тирозинкиназных рецепторов KIT, ERBB4, активирующих передачу сигнала в клетке. Рассматривается также роль сAMP и NF-κB в меланомагенезе. Выявление активирующих мутаций в онкогенах ключевых сигнальных путей позволило применять препараты целенаправленного действия (таргетные), многие из которых показали хороший терапевтический эффект. Особенно перспективно комбинированное лечение меланомы в сочетании с иммунотерапией.

Об авторах

Список литературы

Bertolotto C. Melanoma: from melanocyte to genetic alterations and clinical options. Scientifica (Cairo). 2013; 2013: 635203

Мазуренко Н.Н. Генетические особенности и маркеры меланомы кожи. Успехи молекулярной онкологии. 2014; (2): 26-35

Curtin J.A., Busam K., Pinkel D., Bastian B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 2006; 24 (26): 4340-6.

Kong Y., Si L., Zhu Y., Xu X., Corless C.L., Flaherty K.T. et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin. Cancer Res. 2011; 17 (7): 1684-91.

Read J., Wadt K.A., Hayward N.K. Melanoma genetics. J. Med. Genet. 2016; 53 (1): 1-14.

Aoude L.G., Wadt K.A., Pritchard A.L., Hayward N.K. Genetics of familial melanoma: 20 years after CDKN2A. Pigment Cell Melanoma Res. 2015; 28 (2): 148-60.

Puig-Butille J.A., Escámez M.J., Garcia-Garcia F., Tell-Marti G., Fabra À., Martínez-Santamaría L. et al. Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer. Oncotarget. 2014; 5 (6): 1439-51.

Young R.J., Waldeck K., Martin C., Foo J.H., Cameron D.P., Kirby L. et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res. 2014; 27 (4): 590-600.

Paillerets B.B., Lesueur F., Bertolotto C. A germline oncogenic MITF mutation and tumor susceptibility. Eur. J. Cell Biol. 2014; 93 (1-2): 71-5.

Sekulic A., Haluska P.Jr., Miller A.J., Genebriera De Lamo J., Ejadi S., Pulido J.S. et al. Malignant melanoma in the 21st century: the emerging molecular landscape. Mayo Clin. Proc. 2008; 83 (7): 825-46.

Potrony M., Badenas C., Aguilera P., Puig-Butille J.A., Carrera C., Malvehy J. et al. Update in genetic susceptibility in melanoma. Ann. Transl. Med. 2015; 3 (15): 210.

Potrony M., Puig-Butille J.A., Aguilera P., Badenas C., Tell-Marti G., Carrera C. et al. Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations. JAMA Dermatol. 2016; 152 (4): 405-12.

Kennedy C., ter Huurne J., Berkhout M., Gruis N., Bastiaens M., Bergman W. et al. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J. Invest. Dermatol. 2001; 117 (2): 294-300.

Sturm R.A., Duffy D.L., Box N.F., Chen W., Smit D.J., Brown D.L. et al. The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Res. 2003; 16 (3): 266-72.

Fargnoli M.C., Gandini S., Peris K., Maisonneuve P., Raimondi S. MC1R variants increase melanoma risk in families with CDKN2A mutations: a meta-analysis. Eur. J. Cancer. 2010; 46 (8): 1413-20.

Pogenberg V., Ogmundsdóttir M.H., Bergsteinsdóttir K., Schepsky A., Phung B., Deineko V. et al. Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF. Genes Dev. 2012; 26 (23): 2647-58.

Grill C., Bergsteinsdóttir K., Ogmundsdóttir M.H., Pogenberg V., Schepsky A., Wilmanns M. et al. MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. Hum. Mol. Genet. 2013; 22 (21): 4357-67.

Vachtenheim J., Drdová B. A dominant negative mutant of microphthalmia transcription factor (MITF) lacking two transactivation domains suppresses transcription mediated by wild type MITF and a hyperactive MITF derivative. Pigment Cell Res. 2004; 17 (1): 43-50.

Wellbrock C., Arozarena I. Microphthalmia-associated transcription factor in melanoma development and MAP-kinase pathway targeted therapy. Pigment Cell Melanoma Res. 2015; 28 (4): 390-406.

Testa J.R., Cheung M., Pei J., Below J.E., Tan Y., Sementino E. et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 2011; 43 (10): 1022-5.

Carbone M., Ferris L.K., Baumann F., Napolitano A., Lum C.A., Flores E.G. et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J. Transl. Med. 2012; 10: 179.

Battaglia A. The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment. Clin. Med. Insights Oncol. 2014; 8: 37-47.

Wiesner T., Murali R., Fried I., Cerroni L., Busam K., Kutzner H. et al. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am. J. Surg. Pathol. 2012; 36 (6): 818-30.

Oliveira C., Lourenço G.J., Rinck-Junior J.A., Cintra M.L., Moraes A.M., Lima C.S. Association between genetic polymorphisms in apoptosis-related genes and risk of cutaneous melanoma in women and men. J. Dermatol. Sci. 2014; 74 (2): 135-41.

Thunell L.K., Bivik C., Wäster P., Fredrikson M., Stjernström A., Synnerstad I. et al. MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma. Melanoma Res. 2014; 24 (3): 190-7.

Marzuka-Alcalá A., Gabree M.J., Tsao H. Melanoma susceptibility genes and risk assessment. Methods Mol. Biol. 2014; 1102: 381-93.

Regad T. Targeting RTK Signaling Pathways in Cancer. Cancers (Basel). 2015; 7 (3): 1758-84.

Inamdar G.S., Madhunapantula S.V., Robertson G.P. Targeting the MAPK pathway in melanoma: Why some approaches succeed and other fail. Biochem. Pharmacol. 2010; 80 (5): 624-37.

Kunz М. Oncogenes in melanoma: An update. Eur. J. Cell Biol. 2014; 93 (1-2): 1-10.

Hutchinson K.E., Johnson D.B., Johnson A.S., Sanchez V., Kuba M., Lu P. et al. ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma. Oncotarget. 2015; 6 (26): 22348-60.

Сancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015; 161 (7): 1681-96.

Krauthmammer M., Kong Y., Bacchiocchi A., Evans P., Pornputtapong N., Wu C. et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat. Genet. 2015; 47 (9): 996-1002.

Griewank K.G., Scolyer R.A., Thompson J.F., Flaherty K.T., Schadendorf D., Murali R. Genetic alterations and personalized medicine in melanoma: progress and future prospects. J. Natl. Cancer Inst. 2014; 106 (2): djt435.

Dumaz N. Mechanism of RAF isoform switching induced by oncogenic RAS in melanoma. Small GTPases. 2011; 2 (5): 289-92.

Rodríguez C.I., Setaluri V. Cyclic AMP (cAMP) signaling in melanocytes and melanoma. Arch. Biochem. Biophys. 2014; 563: 22-7.

Kelleher F.C., McArthur G.A. Targeting NRAS in melanoma. Cancer J. 2012; 18 (2): 132-6.

Narita M., Murata T., Shimizu K., Nakagawa T., Sugiyama T., Inui M. et al. A role for cyclic nucleotide phosphodiesterase 4 in regulation of the growth of human malignant melanoma cells. Oncol. Rep. 2007; 17 (5): 1133-9.

Dhawan P., Singh A.B., Ellis D.L., Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-κB and tumor progression. Cancer Res. 2002; 62 (24): 7335-42.

Ueda Y., Richmond A. NF-κB activation in melanoma. Pigment Cell Res. 2006; 19 (2): 112-24.

Madonna G., Ullman C.D., Gentilcore G., Palmieri G., Ascierto P.A. NF-κB as potential target in the treatment of melanoma. J. Transl. Med. 2012; 10: 53.

Amiri K.I., Horton L.W., LaFleur B.J., Sosman J.A., Richmond A. Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implication for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma. Cancer Res. 2004; 64 (14): 4912-8.

Su Y., Amiri K.I., Horton L.W., Yu Y., Ayers G.D., Koehler E. et al. A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin. Cancer Res. 2010; 16 (1): 348-57.

Ohanna M., Giuliano S., Bonet C., Imbert V., Hofman V., Zangari J. et al. Senescent cells develop a PARP-1 and nuclear factor-{kappa}B-associated secretome (PNAS). Genes Dev. 2011; 25 (12): 1245-61.

Мазуренко Н.Н. Генетическая гетерогенность меланомы кожи: новые мишени для селективного воздействия. Злокачественные опухоли. 2015; (4s2): 3-8

Van Raamsdonk C.D., Bezrookove V., Green G., Bauer J., Gaugler L., O’Brien J.M. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009; 457 (7229): 599-602.

Harbour J.W., Onken M.D., Roberson E.D., Duan S., Cao L., Worley L.A. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010; 330 (6009): 1410-3.

Harbour J.W., Roberson E.D., Anbunathan H., Onken M.D., Worley L.A., Bowcock A.M. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat. Genet. 2013; 45 (2): 133-5.

Martin M., Masshofer L., Temming P., Rahmann S., Metz C., Bornfeld N. et al. Exome s equencing identifies recurrent somatic mutations inEIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat. Genet. 2013; 45: 933-6.

Puzanov I., Flaherty K.T. Targeted molecular therapy in melanoma. Semin. Cutan. Med. Surg. 2010; 29 (3): 196-201.

Hodi F.S., Corless C.L., Giobbie-Hurder A., Fletcher J.A., Zhu M., Marino-Enriquez A. et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J. Clin. Oncol. 2013; 31 (26): 3182-90.

Kim K.B., Alrwas A. Treatment of KIT-mutated metastatic mucosal melanoma. Chin. Clin. Oncol. 2014; 3 (3): 35.

Carvajal R.D., Lawrence D.P., Weber J.S., Gajewski T.F., Gonzalez R., Lutzky J. et al. Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. Clin. Cancer Res. 2015; 21 (10): 2289-96.

Prosvicova J., Lukesova S., Kopecky J., Grim J., Papik Z., Kolarova R. et al. Rapid and clinically significant response to masitinib in the treatment of mucosal primary esophageal melanomawith somatic KIT exon 11 mutation involving brain metastases: A case report. Biomed Pap Med Fac Univ. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub. 2015; 159 (4): 695-7.

Johnson D.B., Puzanov I. Treatment of NRAS-mutant melanoma. Curr. Treat. Options Oncol. 2015; 16 (4): 15.

Fedorenko I.V., Gibney G.T., Smalley K.S. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013; 32 (25): 3009-18.

Furue M., Kadono T. Melanoma therapy: Check the checkpoints. J. Dermatol. 2016; 43 (2): 121-4.

Goldinger S.M., Murer C., Stieger P., Dummer R. Targeted therapy in melanoma — the role of BRAF, RAS and KIT mutations. E.J.C. Suppl. 2013; 11 (2): 92-6.

Poynter J.N., Elder J.T., Fullen D.R., Nair R.P., Soengas M.S., Johnson T.M. et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006; 16 (4): 267-73.

Goel V.K., Lazar A.J., Warneke C.L., Redston M.S., Haluska F.G. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J. Invest. Dermatol. 2006; 126 (1): 154-60.

Flaherty K.T., Puzanov I., Kim K.B., Ribas A., McArthur G.A., Sosman J.A. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010; 363 (9): 809-19.

Hauschild A., Grob J.J., Demidov L.V., Jouary T., Gutzmer R., Millward M. et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012; 380 (9839): 358-65.

Van Allen E.M., Wagle N., Sucker A., Treacy D.J., Johannessen C.M., Goetz E.M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014; 4 (1): 94-109.

Spagnolo F., Ghiorzo P., Orgiano L., Pastorino L., Picasso V., Tornari E. et al. BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies. Onco. Targets Ther. 2015; 8: 157-68.

Johnpulle R.A., Johnson D.B., Sosman J.A. Molecular Targeted Therapy Approaches for BRAF Wild-Type Melanoma. Curr. Oncol. Rep. 2016; 18 (1): 6.

Thota R., Johnson D.B., Sosman J.A. Trametinib in the treatment of melanoma. Expert Opin. Biol. Ther. 2015; 15 (5): 735-47.

Eroglu Z., Ribas A. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther. Adv. Med. Oncol. 2016; 8 (1): 48-56.

Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de Braud F., Larkin J. et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 2014; 371 (20): 1877-88.

Robert C., Karaszewska B., Schachter J., Rutkowski P., Mackiewicz A., Stroiakovski D. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 2015; 372 (1): 30-9.

Ribas A., Gonzalez R., Pavlick A., Hamid O., Gajewski T.F., Daud A. et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF ( V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014; 15 (9): 954-65.

Ascierto P.A., McArthur G.A., Dréno B., Atkinson V., Liszkay G., Di Giacomo A.M. et al. Cobimetinib combined with vemurafenib in advanced BRAF (V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016; 17 (9): 1248-60.

Tran K.A., Cheng M.Y., Mitra A., Ogawa H., Shi V.Y., Olney L.P. et al. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy. Drug Des. Devel. Ther. 2016; 10: 43-52.

Sheppard K.E., McArthur G.A. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin. Cancer Res. 2013; 19 (19): 5320-8.

Mirjacic Martinovic K.M., Babovic N.L., Dzodic R.R., Jurisic V.B., Tanic N.T., Konjevic G.M. Decreased expression of NKG2D, NKp46, DNAM-1 receptors, and intracellular perforin and STAT-1 effector molecules in NK cells and their dim and bright subsets in metastatic melanoma patients. Melanoma Res. 2014; 24: 295-304.

Tarazona R., Duran E., Solana R. Natural Killer Cell Recognition of Melanoma: New Clues for a More Effective Immunotherapy. Front Immunol. 2016; 6: 649.

Vennepureddy A., Thumallapally N., Motilal Nehru V., Atallah J.P., Terjanian T. Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma. J. Clin. Med. Res. 2016; 8 (2): 63-75.

Zhu Z., Liu W., Gotlieb V. The rapidly evolving therapies for advanced melanoma-Towards immunotherapy, molecular targeted therapy, and beyond. Crit. Rev. Oncol. Hematol. 2016; 99: 91-9.

Mirzaei H., Gholamin S., Shahidsales S., Sahebkar A., Jaafari M.R., Mirzaei H.R. et al. MicroRNAs as potential diagnostic and prognostic biomarkers in melanoma. Eur. J. Cancer. 2016; 53: 25-32.

Gasque Schoof C.R., Izzotti A., Jasiulionis M.G., Vasques Ldos R. The Roles of miR-26, miR-29, and miR-203 in the Silencing of the Epigenetic Machinery during Melanocyte Transformation. Biomed. Res. Int. 2015; 2015: 634749.

Jayawardana K., Schramm S.J., Tembe V., Mueller S., Thompson J.F., Scolyer R.A. et al. Identification, Review, and Systematic Cross-Validation of microRNA Prognostic Signatures in Metastatic Melanoma. J. Invest. Dermatol. 2016; 136 (1): 245-54.

Zehavi L., Schayek H., Jacob-Hirsch J., Sidi Y., Leibowitz-Amit R., Avni D. MiR-377 targets E2F3 and alters the NF-kB signaling pathway through MAP3K7 in malignant melanoma. Mol. Cancer. 2015; 14: 68.

Lankenau M.A., Patel R., Liyanarachichi S., Maharry S.E., Hoag K.W., Duggan M. et al. MicroRNA-3151 inactivates TP 53 in BRAF-mutated human malignancies. Proc. Natl. Acad. Sci. U S A. 2015; 112 (49): E6744-51.

Ключевые слова