Linhagens de células de melanoma: Mutações e impacto em vias de transdução de sinal / Melanoma cell lines: Mutations and impact on signal transduction pathways

Beatriz Aires Lopes, Anderson Gabriel Ortelan, Alessandra Valeria de Sousa Faria, Carmen Veríssima Ferreira-Halder

Abstract


Linhagens de células tumorais são amplamente utilizadas em pesquisa, uma vez que são úteis para estudos iniciais visando diferentes propósitos, tais como triagem de compostos, ensaios de migração, proliferação, morte celular, expressão gênica, identificação de proteínas específicas, vias de sinalização, dentre outras. Neste aspecto, o conhecimento de características moleculares das linhagens pode auxiliar no planejamento experimental e na interpretação da resposta frente ao estímulo de morte em virtude de um tratamento. Nesta revisão, enfocamos nas alterações moleculares e seus impactos em vias de sinalização, em linhagens de melanoma mais comumente utilizadas como modelos para estudos in vitro. Portanto, essas informações podem ser úteis para ajudar na decisão do modelo celular mais adequado para determinada pergunta científica.

Keywords


Melanoma, linhagens celulares, sinalização celular, mutações

References


Andersen LB, et al. Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nat Genet. 1993;3(2):118-21. doi: 10.1038/ng0293-118.

Antunes F, et al. Fasting boosts sensitivity of human skin melanoma to cisplatin-induced cell death. Biochem Biophys Res Commun. 2017;485(1):16-22. doi: 10.1016/j.bbrc.2016.09.149.

Ascierto PA, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. doi: 10.1186/1479-5876-10-85.

Ballif BA, Blenis J. Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ. 2002;12:397–408.

Barnes TA, Amir E. HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer [published correction appears in Br J Cancer. 2018 Jan 09;:]. Br J Cancer. 2017;117(4):451-460. doi:10.1038/bjc.2017.220

Bonatelli M, et al. Targeting cancer cell metabolism in melanomas: metabolic profiling and 3-bromopyruvate sensitivity screening. 2018;10.1136/esmoopen-2018-EACR25.257

Bos JL. Ras oncogenes in Human Cancer: A Review. Cancer Res. 1989;49(17):4682-9.

Bourland J, et al. Tissue-engineered 3D melanoma model with blood and lymphatic capillaries for drug development. Sci Rep. 2018;8(1):13191. doi:10.1038/s41598-018-31502-6

Breslin, S., & O’Driscoll, L. Three‐dimensional cell culture: The missing link in drug discovery. Drug Discovery Today. 2013;18(5‐6):240–249.

Brohem CA, et al. Artificial skin in perspective: concepts and applications. Pigment Cell Melanoma Res. 2011;24(1):35-50. doi:10.1111/j.1755-148X.2010.00786.x

Brohem CA, et al. Artificial skin in perspective: Concepts and applications. Pigment Cell & Melanoma Res 2011;24(1):35-50.

Carretero J, et al. Growth-associated changes in glutathione content correlate with liver metastatic activity of B16 melanoma cells. Clin Exp Metastasis. 1999;17(7):567-574. doi:10.1023/a:1006725226078

Chabner BA, Roberts TG Jr. Timeline: Chemotherapy and the war on cancer. Nat Rev Cancer. 2005;5(1):65-72. doi:10.1038/nrc1529

Chatzinikolaidou M. Cell spheroids: the new frontiers in in vitro models for cancer drug validation. Drug Discov Today. 2016;21(9):1553-1560. doi:10.1016/j.drudis.2016.06.024

Chen B, et al. Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. eLife. 2017;6. doi: 10.7554/eLife.29795.

Chiba K, et al. Cancer-associated TERT promoter mutations abrogate telomerase silencing. Elife.4:e07918. (2015). doi: 10.7554/eLife.07918.

Ciołczyk-Wierzbicka D, et al. mTOR inhibitor everolimus reduces invasiveness of melanoma cells. Hum Cell. 2020;33(1):88-97. doi:10.1007/s13577-019-00270-4

Cukierman E, et al. Taking cell-matrix adhesions to the third dimension. Science. 2001;294(5547):1708‐1712. doi:10.1126/science.1064829

Davies H, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954.

Deavall DG, et al. Drug-induced oxidative stress and toxicity. J Toxicol. 2012;2012:645460. doi:10.1155/2012/645460

Ding KF, et al. Analysis of variability in high throughput screening data: applications to melanoma cell lines and drug responses. Oncotarget. 2017;8(17):27786-27799.

Dugo M, et al. A melanoma subtype with intrinsic resistance to BRAF inhibition identified by receptor tyrosine kinases gene-driven classification. Oncotarget. 2015;6(7):5118–5133.

Fedorenko I, et al. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013;32:3009–3018. doi: 10.1038/onc.2012.453

Ferraz LS, et al. Targeting mitochondria in melanoma: Interplay between MAPK signaling pathway and mitochondrial dynamics. Biochem Pharmacol. 2020;178:114104. doi: 10.1016/j.bcp.2020.114104.

Figarola JL, et al. Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-naïve and vemurafenib-resistant melanomas. Oncotarget. 2018;9(97):36945-36965. doi: 10.18632/oncotarget.26421.

Garcia VA, et al. Mechanisms of PTEN loss in cancer: it’s all about diversity. Semin Cancer Biol. 2019;59:66-79. doi: 10.1016/j.semcancer.2019.02.001.

Garman B, et al. Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines. 2017;21(7):1936-1952. doi: 10.1016/j.celrep.2017.10.052.

Gibney GT, et al. Paradoxical oncogenesis--the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol. 2013;10(7):390-399. doi:10.1038/nrclinonc.2013.83

Glenister A, et al. A Warburg effect targeting vector designed to increase the uptake of compounds by cancer cells demonstrates glucose and hypoxia dependent uptake. PLoS One. 2019;14(7):e0217712. doi:10.1371/journal.pone.0217712

Gonçalves PR, et al. Violacein induces death of RAS-mutated metastatic melanoma by impairing autophagy process. Tumour Biol. 2016;37(10):14049-14058. doi:10.1007/s13277-016-5265-x

Grimes DR, et al. A method for estimating the oxygen consumption rate in multicellular tumour spheroids. J R Soc Interface. 2014;11(92):20131124.

Halaban R. RAC1 and Melanoma. Clin Ther. 2015;37(3):682–685. doi: 10.1016/j.clinthera.2014.10.027.

Han SY, et al. Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res. 2000;60:3147-3151.

Hemmings, BA & Restuchia DF. Pathway PI3K - PKB/Akt. Cold Spring Harb Perspect Biol. 2012;4(9):a011189. doi: 10.1073/pnas.0900780106.

Hirschhaeuser F, et al. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71(22):6921-6925. doi:10.1158/0008-5472.CAN-11-1457

Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93(4):266-276. doi:10.1093/jnci/93.4.266

Hodis E, et al. A Landscape of Driver Mutations in Melanoma. Cell. 2014;150(2):250-263. doi: 10.1016/j.cell.2012.06.024.

Hofschröer V, et al. Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells. Sci Rep. 2017;7:42369. doi: 10.1038/srep42369.

Horn S, et al. TERT Promoter Mutations in Familial and Sporadic Melanoma. Science. 2013;339(6122): 959-961. doi: 10.1126/science.1230062.

Housman G, et al. Drug resistance in cancer: an overview. Cancers (Basel). 2014;6(3):1769-92. doi: 10.3390/cancers6031769.

Hubbard SR, Miller WT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007;19(2):117–123. doi: 10.1016/j.ceb.2007.02.010.

Ikediobi ON, et al. Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol Cancer Ther. 2006;5(11):2606-12. doi: 10.1158/1535-7163.MCT-06-0433.

Jang GH, et al. Low inducible expression of p21Cip1 confers resistance to paclitaxel in BRAF mutant melanoma cells with acquired resistance to BRAF inhibitor. Mol Cell Biochem. 2015;406(1-2):53-62. doi:10.1007/s11010-015-2423-1

Keniry M & Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene. 2008;(27):5477–5485. doi: 10.1038/onc.2008.248.

Kiuru M & Busam KJ. The NF1 gene in tumor syndromes and melanoma. Lab Invest. 97(2): 146–157. (2017). doi: 10.1038/labinvest.2016.142.

Klimkiewicz K, et al. A 3D model of tumour angiogenic microenvironment to monitor hypoxia effects on cell interactions and cancer stem cell selection. Cancer Lett. 2017;396:10-20. doi: 10.1016/j.canlet.2017.03.006.

Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. U. S. A., 1971;68:820-823. doi: 10.1073/pnas.68.4.820.

Krauthammer M, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44(9):1006–1014. doi: 10.1038/ng.2359.

Larkin J, et al. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma. N Engl J Med. 371:1867-1876. (2014). doi: 10.1056/NEJMoa1408868.

Lee S, et al. Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity. International Journal of Molecular Sciences. 2020;21(3):1102. doi: 10.3390/ijms21031102.

Lee SY, Bissell MJ. A Functionally Robust Phenotypic Screen that Identifies Drug Resistance-associated Genes Using 3D Cell Culture. Bio Protoc. 2018;8(22):e3083. doi:10.21769/BioProtoc.3083

Li J, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 275:1943-1947 (1997). doi: 10.1126/science.275.5308.1943.

Li Y, et al. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas. Proc Natl Acad Sci U S A. 20166;113(50):14402–14407. doi: 10.1073/pnas.1611106113.

Lin Y, Zheng Y. Approaches of targeting Rho GTPases in cancer drug discovery. Expert Opin Drug Discov. 2015;10(9):991–1010. doi: 10.1517/17460441.2015.1058775.

Lionarons DA, et al. RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance. Cancer Cell. 2019;36(1):68-83. doi: 10.1016/j.ccell.2019.05.015.

Liu D, et al. Mechanisms of Resistance to Immune Checkpoint Blockade. Am J Clin Dermatol. 2019;20(1):41‐54. doi:10.1007/s40257-018-0389-y

Long GV et al. Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. N Engl J Med. 2014;371:1877-1888. doi: 10.1056/NEJMoa1406037.

Longati P, et al. 3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing. BMC Cancer. 2013;13:95. doi: 10.1186/1471-2407-13-95.

Luo W, Semenza GL. Emerging roles of PKM2 in cell metabolism and cancer progression. Trends Endocrinol Metab. 2012;23(11):560-6

Maciejowsk J, Lange T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol. 2017;18(3):175–186. doi: 10.1038/nrm.2016.171.

Maciejowski J, de Lange T. Telomeres in cancer: tumour suppression and genome instability [published correction appears in Nat Rev Mol Cell Biol. 2019 Apr;20(4):259]. Nat Rev Mol Cell Biol. 2017;18(3):175-186. doi:10.1038/nrm.2016.171

Maertens O, et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discovery. 2013;3(3). doi: 10.1158/2159-8290.CD-12-0313.

Mahimainathan L, Choudhury GG. Inactivation of Platelet-Derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase. J Biol Chem. 2004;279(15):15258-68. doi: 10.1074/jbc.M314328200.

Malumbres, M., Barbacid, M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3:459–465. doi: 10.1038/nrc1097.

Manzano JL, et al., Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med. 2016;4(12):237. doi: 10.21037/atm.2016.06.07.

Mehta G, et al. Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. Journal of Controlled Release. 2012;164(2):192–204.

Menshykau, D. Emerging technologies for prediction of drug candidate efficacy in the preclinical pipeline. Drug Discovery Today. 2017;22(11):1598–1603.

Moreira AF, et al. Stimuli-responsive mesoporous silica nanoparticles for cancer therapy: A review. Microporous and Mesoporous Materials. 2016;236:141-157

Morrison DK. MAP Kinase Pathways. Cold Spring Harb Perspect Biol. 2012;4(11):a011254. doi: 10.1101 / cshperspect.a011254

Nagore E, et al. TERT promoter mutations in melanoma survival. Int J Cancer. 2016;139(1):75-84. doi: 10.1002/ijc.30042.

Nath S, Devi GR. Three-dimensional culture systems in cancer research: Focus on tumor spheroid model. Pharmacol Ther. 2016;163:94‐108. doi:10.1016/j.pharmthera.2016.03.013

Nathanson KL, et al., Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor Dabrafenib (GSK2118436). Clin Cancer Res. 2013;19(17):4868–4878. doi: 10.1158/1078-0432.CCR-13-0827.

Nazarian R, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326): 973–977. doi: 10.1038/nature09626.

Nervi C, et al. Epigenetic treatment of solid tumours: a review of clinical trials. Clin Epigenetics. 2015;7:127. doi:10.1186/s13148-015-0157-2

Nissan MH, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 2014;74(8):2340-50. doi: 10.1158/0008-5472.CAN-13-2625.

Niu N, Wang L. In vitro human cell line models to predict clinical response to anticancer drugs. Pharmacogenomics. 2015;16(3):273–285.

Nunes AS, et al. 3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs. Biotechnol Bioeng. 2019;116(1):206‐226. doi:10.1002/bit.26845

Nyga A, et al. 3D tumour models: novel in vitro approaches to cancer studies. J Cell Commun Signal. 2011;3:239–248. doi: 10.1007/s12079-011-0132-4

Overwijk WW, Restifo NP. B16 as a mouse model for human melanoma. Curr Protoc Immunol. 2001;Chapter 20:Unit-20.1. doi:10.1002/0471142735.im2001s39

Pampaloni F, et al. The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol. 2007;8(10):839-845. doi:10.1038/nrm2236

Paraiso KHT, et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71(7):2750–2760. doi: 10.1158/0008-5472.CAN-10-2954.

Petit V, et al. C57BL/6 congenic mouse NRASQ61K melanoma cell lines are highly sensitive to the combination of Mek and Akt inhibitors in vitro and in vivo. Pigment Cell Melanoma Res. 2019;32(6):829-841. doi: 10.1111/pcmr.12807.

Pratilas CA, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 2008;68:9375-83.

Qin Y, et al. Hypoxia-Driven Mechanism of Vemurafenib Resistance in Melanoma. Mol Cancer Ther. 2016;15(10):2442-2454. doi: 10.1158/1535-7163.MCT-15-0963.

Roberts RE. The extracellular signal-regulated kinase (ERK) pathway: a potential therapeutic target in hypertension. J Exp Pharmacol. 2012;4:77‐83. Published 2012 Aug 1. doi:10.2147/JEP.S28907

Rocha-Brito KJP, et al. Calix[6]arene diminishes receptor tyrosine kinase lifespan in pancreatic cancer cells and inhibits their migration and invasion efficiency. Bioorg Chem. 2020;100:103881. doi:10.1016/j.bioorg.2020.103881

Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat. 2011;14(3):191-201. doi:10.1016/j.drup.2011.03.001

Rushworth LK, et al. Regulation and role of Raf-1/B-Raf heterodimerization. Mol Cell Biol. 2006;26(6):2262–2272. doi: 10.1128/MCB.26.6.2262-2272.2006

Sandri S, et al. Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation. Pharmacol Res. 2016;111:523-533. doi: 10.1016/j.phrs.2016.07.017.

Sauter ER, et al. Cyclin D1 is a candidate oncogene in cutaneous melanoma. Cancer Res. 2002;62(11):3200-3206.

Schadendorf D, et al. Membrane transport proteins associated with drug resistance expressed in human melanoma. Am J Pathol. 1995;147(6):1545-52.

Shain AH, Bastian BC. From melanocytes to melanomas [published correction appears in Nat Rev Cancer. 2020;20(6):355]. Nat Rev Cancer. 2016;16(6):345-358. doi:10.1038/nrc.2016.37

Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27-36. doi:10.1093/carcin/bgp220

Singh K, Mehta S. The clinical development process for a novel preventive vaccine: An overview. J Postgrad Med. 2016;62(1):4-11. doi:10.4103/0022-3859.173187

Smalley KS, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther. 2008;7(9):2876-83. doi: 10.1158/1535-7163.MCT-08-0431.

Smalley KSM, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas. Mol Cancer Ther. 2008;7(9):2876–2883. doi: 10.1158/1535-7163.MCT-08-0431.

Sonveaux P. ROS and radiotherapy: more we care. Oncotarget. 2017;8(22):35482-35483. doi:10.18632/oncotarget.16613

Špaková I, et al. Hypoxia factors suppression effect on the energy metabolism of a malignant melanoma cell SK-MEL-30. Eur Rev Med Pharmacol Sci. 2020;24(9):4909-4920. doi:10.26355/eurrev_202005_21180

Sun C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508(7494):118-124. doi: 10.1038/nature13121.

Tanami H, et al. Involvement of overexpressed wild-type BRAF in the growth of malignant melanoma cell lines. Oncogene. 2004;23(54):8796-804. doi: 10.1038/sj.onc.1208152.

Tate JG, et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019;47(D1):D941-D947. doi: 10.1093/nar/gky1015.

Trager MH, et al. Biomarkers in melanoma and non-melanoma skin cancer prevention and risk stratification. Exp Dermatol. 2020;10.1111/exd.14114. doi:10.1111/exd.14114

Trédan O, et al. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 2007;99(19):1441-1454. doi:10.1093/jnci/djm135

van Staveren WC, et al. Human cancer cell lines: Experimental models for cancer cells in situ? For cancer stem cells?. Biochim Biophys Acta. 2009;1795(2):92-103. doi:10.1016/j.bbcan.2008.12.004

Villanueva J, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by co-targeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683–695. doi: 10.1016/j.ccr.2010.11.023.

Wagle N, et al. MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition. Cancer Discovery. 2014;4(1). doi: 10.1158/2159-8290.CD-13-0631.

Warburg, O. On the origin of cancer cells. Science. 1956;123:309–314.

Ware MJ, et al. Generation of an in vitro 3D PDAC stroma rich spheroid model. Biomaterials. 2016;108:129-42. doi: 10.1016/j.biomaterials.2016.08.041.

Watson IR, et al. The RAC1 P29S Hotspot Mutation in Melanoma Confers Resistance to Pharmacological Inhibition of RAF. Cancer Res. 2014;74(17):4845–4852. doi: 10.1158/0008-5472.CAN-14-1232-T.

Wenzel C, et al. 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions. Exp Cell Res. 2014;323(1):131-43. doi: 10.1016/j.yexcr.2014.01.017.

Wigerup C, et al Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. 2016;164:152-169. doi:10.1016/j.pharmthera.2016.04.009

Xing F, et al. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene. 2012;31(4):446-57. doi: 10.1038/onc.2011.250.

Yamada K, et al. Factors influencing [F-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) accumulation in melanoma cells: is FDG a substrate of multidrug resistance (MDR)? J Dermatol. 2005;32(5):335-45. doi: 10.1111/j.1346-8138.2005.tb00904.x.

Yang Y, et al. p38 and JNK MAPK, but not ERK1/2 MAPK, play important role in colchicine-induced cortical neurons apoptosis. European Journal of Pharmacology. 20077;576(1–3):26-33. doi: 10.1016/j.ejphar.2007.07.067.

Yoshida A, et al. Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended Inhibition of CDK4/6. Cancer Res. 2016;76(10):2990–3002. doi: 10.1158/0008-5472.CAN-15-2931.

Zaidi S, et al. Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents. Mol Ther. 2015;23(5):845-856. doi: 10.1038/mt.2014.253.

Zhao Y, et al. MicroRNA-33b inhibits cell proliferation and glycolysis by targeting hypoxia-inducible factor-1α in malignant melanoma. Exp Ther Med. 2017;14(2):1299-1306. doi: 10.3892/etm.2017.4702.

Zips D, et al. New anticancer agents: In vitro and in vivo evaluation. In Vivo, 2005;19(1):1–7.

Alonso-Curbelo D, et al. RAB7 counteracts PI3K-driven macropinocytosis activated at early stages of melanoma development. Oncotarget. 2015;6(14):11848-11862. doi:10.18632/oncotarget.4055

García-Fernández M, et al. Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5. Autophagy. 2016;12(10):1776-1790. doi:10.1080/15548627.2016.1199301




DOI: https://doi.org/10.34119/bjhrv3n4-291

Refbacks

  • There are currently no refbacks.