Abstract
Cutaneous melanoma is a highly heterogeneous malignancy, which characterized by low effectiveness of chemotherapeutic antitumor agents. 50% of melanomas have a somatic mutation in BRAF oncogene, leading to uncontrolled activation of mitogen-activated protein kinase signaling cascade ensuring the proliferation and survival of tumor cells. The blocking of the BRAF gene mutation effects seemed to be a reasonable way to increase the effectiveness of melanoma therapy. However, the effectiveness of melanoma treatment in many patients is limited up to six months due to the development of acquired resistance. Acquired chemoresistance is related to the reactivation of signal pathways involved in the control of cell proliferation. Besides, several BRAF-positive melanomas exhibit intrinsic resistance due to mutations in tumor suppressor genes. Unveiling molecular mechanisms of chemoresistance to targeted therapy will allow developing more effective strategies for cancer diseases. This paper provides a review of the literature and our data as well as the results of clinical studies on a variety of resistance mechanisms and strategies for their elimination.
Authors and affiliations
T.G. Ruksha, D.S. Zemtsov, S.N. Lavrentiev, N.V. Palkina, A.R. Yessimbekova Professor V. F. Voino-Yasenetsky Krasnoyarsk State Medical University, Partizana Zheleznyaka str., 1, Krasnoyarsk, 660022, Russian Federation E-mail: rector@krasgmu.ru Semyon Lavrentiev – PhD student of the Pathological Physiology Department. Krasnoyarsk State Medical University. Tel.: +7 (3912) 28-36-49. E-mail: semyonlavrentev@mail.ru. ORCID: 0000-0002-2214-1336 Nadezhda Palkina – assistant of the Department of pathological physiology. Krasnoyarsk State Medical University. Candidate of medical Sciences. Tel.: +7 (3912) 28-36-49. E-mail: mosmannv@yandex.ru. ORCID: 0000-0002-6801-3452 Alexandra Yesimbekova – PhD student of the Pathological Physiology Department. Krasnoyarsk State Medical University. Тел.: +7 (3912) 28-36-49. E-mail: aleksandra.esimbekova.96@mail.ru. ORCID: 0000-0001-6363-5941
References
Maverakis E., Cornelius L.A., Bowen G.M., Phan T., Patel F.B., Fitzmaurice S., He Y., Burrall B., Duong C., Kloxin A.M., HawaSultani H., Wilken R., Martinez S.R., Patel F. Metastatic melanoma – a review of current and future treatment options. Acta Derm Venereol. 2015; 95 (5): 516–24. https://doi.org/10.2340/00015555-2035.
Atkins M.B., Hsu J., Lee S., Cohen G.I., Flaherty L.E., Sosman J.A., Sondak V.K., Kirkwood J.M. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J. Clin. Oncol. 2008; 26 (35): 5748–54.
Middleton M.R., Grob J.J., Aaronson N., Fierlbeck G., Tilgen W., Seiter S., Gore M., Aamdal S., Cebon J., Coates A., Dreno B., Henz M., Schadendorf D., Kapp A., Weiss J., Fraass U., Statkevich P., Muller M., Thatcher N. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J. of Clinical Oncology. 2000; 18 (1): 158–66.
Kaprin A.D., Starinskij V.V., Petrova G.V. Zlokachestvennye novoobrazovanija v Rossii v 2018 godu (zabolevaemost' i smertnost'). M.: MNIOI im. P.A. Gertsena – filial FGBU «NMITs radiologii» Minzdrava Rossii, 2019; 250. [A.D. Kaprin, V. Starinsky, and G. V. Petrova. Malignant neoplasms in Russia in 2018 (morbidity and mortality). M.: MNIOI im. P.A. Gercena filial FGBU «NMIC radiologii» Minzdrava Rossii, 2019; 250 (in Russian)]
Artjuhov I.P., Gavriljuk D.V., Dyhno Ju.A., Ruksha T.G. Zabolevemost' melanomoj kozhi vzroslogo naselenija Krasnojarskogo kraja. Sibirskoe meditsinskoe obozrenie. 2013; 6 (84): 37–42. [Artyukhov I.P., Gavrilyuk D.V., Dihno J.A., Ruksha T.G. Zabolevaemosti melanoma of the skin of the adult population of the Krasnoyarsk territory. Siberian medical review. 2013; 6 (84): 37–42 (In Russian)]
Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. 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. https://doi.org/10.3322/caac.21492.
Cascinelli N., Belli F., MacKie R.M., Santinami M., Bufalino R., Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet. 2001; 15; 358 (9285): 866–9.
Davies H., Bignell G.R., Cox C., Stephens P., Edkins S., Clegg S., Teague J., Woffendin H., Garnett M.J., Bottomley W., Davis N., Dicks E., Ewing R., Floyd Y., Gray K., Hall S., Hawes R., Hughes J., Kosmidou V., Menzies A., Mould C., Parker A., Stevens C., Watt S., Hooper S., Wilson R., Jayatilake H., Gusterson B.A., Cooper C., Shipley J., Hargrave D., Pritchard-Jones K., Maitland N., Chenevix-Trench G., Riggins G.J., Bigner D.D., Palmieri G., Cossu A., Flanagan A., Nicholson A., Ho J.W., Leung S.Y., Yuen S.T., Weber B.L., Seigler H.F., Darrow T.L., Paterson H., Marais R., Marshall C.J., Wooster R, Stratton M.R., Mutations of the BRAF gene in human cancer. Nature. 2002; 417 (6892): 949–54. https://doi.org/10.1038/nature00766
Janet L., Maldonado., Jane Fridlyand, Hetal Patel, Ajay N. Jain, Klaus Busam, Toshiro Kageshita, Tomomichi Ono, Donna G. Albertson, Dan Pinkel, Boris C. Bastian. Determinants of BRAF Mutations in Primary Melanomas. J. Natl. Cancer Inst. 2003; 95 (24): 1878–90. https://doi.org/10.1093/jnci/djg123
Aksenenko M.B., Kirichenko A.K., Ruksha T.G. Russian study of morphological prognostic factors characterization in BRAF-mutant cutaneous melanoma. Pathol Res Pract. 2015; 211 (7): 521–7.
Orlova K.V., Harkevich G.Ju., Utjashev I.A., Demidov L.V. Personalizirovannaja terapija metastaticheskoj melanomy kozhi. Effektivnaja farmakoterapija. 2016; 39: 16–21. [Orlova K.V., Kharkevich G.Yu., Utyashev I.A., Demidov L.V. Personalized Therapy for Metastatic Skin Melanoma. Jeffektivnaja farmakoterapija. 2016; 39: 16–21 (in Russian)]
Tsai J., Lee J.T., Wang W., Zhang J., Cho H., Mamo S., Bremer R., Gillette S., Kong J., Haass N. K., Sproesser K., Li L., Smalley K. S. M., Fong D., Zhu Y-L.,Marimuthu A., Nguyen H., Lam B., Liu J., Cheung I., Rice J., Suzuki Y.,Luu C.,Settachatgul C., Shellooe R., Cantwell J., Kim S-H., Schlessinger J., Zhang K. Y. J., West B.L., Powell B., Habets G., Zhang C., Ibrahim P. N.,Hirth P,Artis D.R., Herlyn M.,Bollag G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci. 2008; 105 (8): 3041–6. https://doi.org/10.1073/pnas.0711741105
McArthur G.A., Chapman P.B., Robert C., Larkin J., Haanen J.B., Dummer R., Ribas A., Hogg D., Hamid O., Ascierto P.A., Garbe C., Testori A., Maio M., Lorigan P., Lebbé C., Jouary T., Schadendorf D., O’Day S.J., Kirkwood J.M., Eggermont A.M., Dréno B., Sosman J.A., Flaherty K.T., Yin M., Caro I., Cheng S., Trunzer K., Hauschild A. Safety and efficacy of vemurafenib in BRAF (V600E) and BRAF (V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. The Lancet Oncology. 2014; 15 (3): 323–32. https://doi.org/10.1016/S1470-2045(14)70012-9
Amaral T., Sinnberg T., Meier F., Krepler C., Levesque M., Niessner H., Garbe C. The mitogen-activated protein kinase pathway in melanoma part I – activation and primary resistance mechanisms to BRAF inhibition. European J. of Cancer. 2017; 73: 93–101. https://doi.org/10.1016/j.ejca.2016.12.010
Hugo W., Shi H., Sun L., Piva M., Song C., Kong X., Moriceau G., Hong A., Dahlman K.B., Johnson D.B., Sosman J.A., Ribas A., Lo R.S. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015; 162 (6): 1271–85. https://doi.org/10.1016/j.cell.2015.07.061
Eliezer M. Van Allen., Wagle N., Sucker A., Treacy D.J., Johannessen C.M., Goetz E.M., Place C.S., Taylor-Weiner A., Whittaker S., Kryukov G.V., Hodis E., Rosenberg M., McKenna A., Cibulskis K., Farlow D., Zimmer L., Hillen U., Gutzmer R., Goldinger S.M., Ugurel S., Gogas H.J., Egberts F., Berking C., Trefzer U., Loquai C., Weide B., Hassel J.C., Gabriel S.B., Carter S.L., Getz G., Garraway L.A., Schadendorf D. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discovery. 2014; 4 (1): 94–109. https://doi.org/10.1158/2159-8290.CD-13-0617
Johnson D.B., Menzies A.M., Zimmer L., Eroglu Z., Ye F., Zhao S., Rizos H., Sucker A., Scolyer R.A., Gutzmer R., Gogas H., Kefford K.F., Thompson J.F., Becker J.C., Berking C., Egberts F., Loquai C., GoldingerS.M., Pupo G.M., Hugo W., Kong X., Garraway L.A., Sosman J.A., Ribas A., Lo R.S., Long G.V., Schadendorf D. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Clinical Cancer Research. 2015; 51 (18): 2792–9. https://doi.org/10.1016/j.ejca.2015.08.022.
Shen-hsi Yang., Sharrocks A.D., Whitmarsh A.J. MAP kinase signalling cascades and transcriptional regulation. Gene. 2013; 513: 1–13. https://doi.org/10.1016/j.gene.2012.10.033
Gray-Schopfer V., Wellbrock C., Marais R. Melanoma biology and new targeted therapy. Nature. 2007; 445 (7130): 851–7. https://doi.org/10.1038/nature05661
Demidov L.V., Utjashev I.A., Harkevich G.Ju. Podhody k diagnostike i terapii melanomy kozhi: erapersonalizirovannoĭ meditsiny. Consilium Medicum. Dermatologija. 2013; 2 (3): 42–7. [Demidov L.V., Utyashev I.A., Kharkevich G.Yu. Approaches to the diagnosis and therapy of cutaneous melanoma: repersonalization medicine. ConsiliumMedicum. Dermatology. 2013; 2 (3): 42–7 (in Russian)]
Wagle N., Van Allen E.M., Treacy D.J, Frederick D.T., Cooper Z.A., Taylor-Weiner A., Rosenberg M., Goetz E.M., Sullivan R.J., Farlow D.N., Friedrich D.C., Anderka K., Perrin D., Johannessen C.M., McKenna A., Cibulskis K., Kryukov G., Hodis E., Lawrence D.P., Fisher S., Getz G., Gabriel S.B., Carter S.L., Flaherty K.T., Wargo J.A., Garraway L.A. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Disc. 2014; 4 (1): 61–8. https://doi.org/10.1158/2159-8290.CD-13-0631
Atzori MG., Ceci C., Ruffini F., Trapani M., Barbaccia M.L., Tentori L., D’Atri S., Lacal P.M., Graziani G. Role of VEGFR-1 in melanoma acquired resistance to the BRAF inhibitor vemurafenib. Journal of cellular and molecular medicine. 2019; 24: 465–75. https://doi.org/10.1111/jcmm.14755
Wang J., Sinnberg T., Niessner H., Dölker R., Sauer B., Kempf W.E., Meier F., Leslie N.R., Schittek B. PTEN regulates IGF-1R-mediated therapy resistance in melanoma. Pigment Cell Melanoma Res. 2015; 28: 572–89. https://doi.org/10.1111/pcmr.12390
Ng Y.K., Lee J.Y., Supko K.M., Khan A.S., Torres S.M., Berwick M., Ho J., Kirkwood J.M., Siegfried J.M., Stabile L.P. Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res. 2014; 24 (3): 207–18. https://doi.org/10.1097/CMR.0000000000000060
Yadav V., Zhang X., Liu J., Estrem S., Li S., Gong X-Q., Buchanan S., Henry J.R., Starling J.J., Peng S-B. Reactivation of Mitogen-activated Protein Kinase (MAPK) pathway by FGF Receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J. Biol. Chem. 2012; 287 (33): 28087–98. https://doi.org/10.1074/jbc.M112.377218.
Poulikakos P.I., Persaud Y., Janakiraman M., Kong X., Ng C., Moriceau G., Shi H., Atefi M., Titz B., Gabay M.T., Salton M., Dahlman K.B., Tadi M., Wargo J.A., Flaherty K.T., Kelley M.C., Misteli T., Chapman P.B., Sosman J.A., Graeber T.G., Ribas A., Lo R.S., Rosen N., Solit D.B. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011; 480 (7377): 387–90. https://doi.org/10.1038/nature10662
Wagle N., Emery C., Berger MF., Davis MJ., Sawyer A., Pochanard P., Kehoe SM., Johannessen CM., Macconaill LE., Hahn WC., Meyerson M., Garraway LA. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 2011; 29 (22): 3085–96. https://doi.org/10.1200/JCO.2010.33.2312
Moriceau G., Hugo W., Hong A., Shi H., Kong X., Yu C.C., Koya R.C., Samatar A.A., Khanlou N., Braun J., Ruchalski K., Seifert H., Larkin J., Dahlman K.B., Johnson D.B., Algazi A., Sosman J.A., Ribas A., Lo R.S. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell. 2015; 27 (2): 240–56. https://doi.org/10.1016/j.ccell.2014.11.018.
Mazurenko N.N. Geneticheskie osobennosti i markery melanomy kozhi. Uspehi molekuljarnoj onkologii. 2014; 1 (2): 26–35. [Mazurenko N.N. Genetic alterations and markers of melanoma. Advances in Molecular Oncology. 2014; 1 (2): 26–35 (in Russian)]
Rajkumar S., Watson I.R. Molecular characterization of cutaneous melanoma: creating a framework for targeted and immune therapies. Br. J. Cancer. 2016; 115 (2): 145–55. https://doi.org/10.1038/bjc.2016.195
Fedorenko I.V., Gibney G.T., Keiran S.M. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013; 32 (25): 3009–18. https://doi.org/10.1038/onc.2012.453.
Grimaldi A.M., Simeone E., Festino L., Vanella V., Marco Palla M., Ascierto P.A. Novel mechanisms and therapeutic approaches in melanoma: targeting the MAPK pathway. Discovery Medicine. 2015; 19 (107): 455–61.
Jiang C.C., Lai F., Thorne R.F., Yang F., Liu H., Hersey P., Zhang X.D. MEK-independent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2011; 17 (4): 721–30. https://doi.org/10.1158/1078-0432.CCR-10-2225
Zhulikov Ja.A., Samojlenko I.V., Demidov L.V. Mehanizmy rezistentnosti metastaticheskoj melanomy kozhi k anti-PD-L terapii. Rossijskij bioterapevticheskij zhurnal. 2018; 1 (17): 34–46. [Zhulikov Ya.A., Samoylenko I.V., Demidov L.V. Mechanisms of resistance to anti-PD-1 therapy in metastatic cutaneous melanoma. Rossijskij bioterapevticheskij zhurnal. 2018; 1 (17): 34–46 (in Russian)]
Smalley K.S., Haass N.K., Brafford P.A., Lioni M., Flaherty K.T., Herlyn M. Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther. 2006; 5 (5): 1136–44.
Gopal Y.N., Deng W., Woodman S.E., Komurov K., Ram P., Smith P.D., Davies M.A.Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res. 2010; 70 (21): 8736–47. https://doi.org/10.1158/0008-5472.CAN-10-0902.
Paraiso K.H.T., Xiang Y., Rebecca V.W., Abel E.V., Chen Y.A., Munko A.C., Wood E., Fedorenko I.V., Sondak V.K., Anderson A.R.A., Ribas A., Palma M.D., Nathanson K.L., Koomen J.M., Messina J.L., Smalley K.S.M. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011; 71 (7): 2750–60. https://doi.org/10.1158/0008-5472.
Lacouture M.E., Duvic M., Hauschild A., Prieto V.G., Robert C., Schadendorf D., Kim C.C., McCormack C.J., Myskowski P.L., Spleiss O., Trunzer K., Su F., Nelson B., Nolop K.B., Grippo J.F., Lee R.J., Klimek M.J., Troy J.L., Joe A.K. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013; 18 (3): 314–22. https://doi.org/10.1634/theoncologist.2012-0333.
Solit DB., Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J. Med. 2011; 364 (8): 772–4. https://doi.org/10.1056/NEJMcibr1013704.
Long G.V., Eroglu Z., Infante J., Patel S.J. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib. Clin. Oncol. 2018; 36 (7): 667–73. https://doi.org/10.1200/JCO.2017.74.1025
Strojakovskij D.L., Abramov M.E., Demidov L.V., Novik A.V., Orlova K.V., Protsenko S.A, Samojlenko I.V., Trofimova O.P., Harkevich G.Ju., Jurchenkov A.N. Zlokachestvennye opuholi. 2019; 9 (3s2): 776. https://doi.org/10.18027/2224-5057-2019-9-3s2-243-258 [Stroyakovsky D.L., Abramov M.E., Demidov L.V., Novik A.V., Orlova K.V., Protsenko S.A, Samoylenko I.V., Trofimova O.P., Harkevich G.Yu., Yurchenkov A.N. Zlokačestvennye opuholi. 2019; 9 (3s2): 776. https://doi.org/10.18027/2224-5057-2019-9-3s2-243-258 (in Russian)]
Kohno M., Tanimura S., Ozaki K. Targeting the extracellular signal-regulated kinase pathway in cancer therapy. Biol. Pharm. Bull. 2011; 34 (12): 1781–4.
Ferguson J., Arozarena I., Ehrhardt M., Wellbrock C. Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene. 2013; 32 (1): 86–96. https://doi.org/10.1038/onc.2012.25.
Siroy A.E., Davies M.A., Lazar A.J. The PI3K-AKT Pathway in Melanoma. Genetics of Melanoma. Cancer Genetics. Springer, New York, NY. 2016; 165–80. https://doi.org/10.1007/978-1-4939-3554-3_7.
Watson I.R., Li L., Cabeceiras P.K., Mahdavi M., Gutschner T., Genovese G., Wang G., Fang Z., Tepper J.M., Stemke-Hale K., Tsai K.Y., Davies M.A., Mills G.B., Chin L. The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. 2014; 74: 4845–52. https://doi.org/10.1158/0008-5472.CAN-14-1232-T
Whittaker S.R., Theurillat J.P., Van Allen E., Wagle N., Hsiao J., Cowley G.S., Schadendorf D., Root D.E., Garraway L.A. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 2013; 3: 350–62. https://doi.org/10.1158/2159-8290.CD-12-0470.
Smalley K.S.M., Lioni M., Dalla Palma M., Xiao M., Desai B., Egyhazi S., Hansson J., Wu H., King A.J., Van Belle P., Elder D.E., Flaherty K.T., Herlyn M., Nathanson K.L. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther. 2008; 7 (9): 2876–83. https://doi.org/10.1158/1535-7163.MCT-08-0431
Paraiso K.H., Fedorenko I.V., Cantini L.P., Munko A.C., Hall M., Sondak V.K., Messina J.L., Flaherty K.T., Smalley K.S. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br. J. Cancer. 2010; 102 (12): 1724–30. https://doi.org/10.1038/sj.bjc.6605714
Curtin J.A., Fridlyand J., Kageshita T., Patel H.N., Busam K.J., Kutzner H., Cho K-H., Aiba S., Bröcker E-B., LeBoit P.E., Pinkel D., Bastian B.C. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 2005; 353 (20): 2135–47. https://doi.org/10.1056/NEJMoa050092
Diaz-Martinez M., Benito-Jardón L., Alonso L., Koetz-Ploch L., Hernando E., Teixidó J. miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma. Cancer Res. 2018; 78 (4): 1017–30.