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Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland
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Cells 2020, 9(1), 142; https://doi.org/10.3390/cells9010142
Received: 29 November 2019 / Revised: 29 December 2019 / Accepted: 3 January 2020 / Published: 7 January 2020
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Cutaneous Melanoma)
The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line- and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKThigh resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies. View Full-Text
Keywords: acquired resistance; vemurafenib; trametinib; melanoma plasticity; reversible transcriptional reprogramming; growth factor dependence; AXL; NGFR; RBMX; patient-to-patient variability acquired resistance; vemurafenib; trametinib; melanoma plasticity; reversible transcriptional reprogramming; growth factor dependence; AXL; NGFR; RBMX; patient-to-patient variability
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Hartman, M.L.; Sztiller-Sikorska, M.; Gajos-Michniewicz, A.; Czyz, M. Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity. Cells 2020, 9, 142.

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