Molecular characterization of melanoma cells that present plastic resistance to MAPK inhibitors

BARON, ANTONELA; MADORSKY ROWDO, FLORENCIA PAULA; MORDOH, JOSE; VON EUW, ERIKA MARÍA

Buenos Aires

Congreso; LXII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

MOLECULAR CHARACTERIZATION OF MELANOMA CELLS THAT PRESENT PLASTIC RESISTANCE TO MAPK INHIBITORSNearly one-half of melanoma patients harbor the BRAFV600 driver mutation, the most common being BRAFV600E, which leads to the activation of proliferative and survival pathways. The development of BRAF V600 and MEK inhibitors constitutes a breakthrough in the treatment of patients with BRAF-mutated metastatic melanoma. However, although there is an increase in overall survival, these patients generally confront recurrence, and several resistance mechanisms have already been described. We studied the effects PLX4032 (BRAFV600 inhibitor) and GDC-0973 (MEK inhibitor) long-term treatment on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of long-term in vitro treatment with PLX4032 and/or GDC-0973, the majority of the melanoma cells died whereas some remained viable and quiescent. We named this population SUR cells. Strikingly, discontinuing treatment of SUR cells with MAPK inhibitors allowed the population to regrow and these cells retained drug sensitivity equal to that of parental cells. SUR cells had increased expression levels of CD271 and ABCB5 and presented senescence associated characteristics. In order to characterize SUR cells we performed Whole Exome Sequencing, RNAseq experiments, expression microarrays and reverse phase protein arrays (RPPA) comparing parental and SUR cells. Even though SUR cells do not present mutations associated with resistance, consistently with their plastic phenotype, RNA seq experiments showed that SUR cells present changes in the expression of 1509 genes (p