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Predominance of MAPK reactivation in early resistance to debrafenib/trametinib combination therapy of BRAF mutant metastatic melanoma.

ABSTRACT: One third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within six months. Treatment options for these patients remain limited. Here we analyse twenty BRAFV600 mutant melanoma metastases derived from 10 patients treated with the combination of debrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumors and MAPK reactivation occurred in 9/10 tumors, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein confers resistance to combination therapy, highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (e.g. RCA1 and AKT3) that activate the MAPK and P13K pathways and are thus predicted to diminish response to MAPK inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61992 | GEO | 2014/12/03

SECONDARY ACCESSION(S): PRJNA262903

REPOSITORIES: GEO

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Project description:Fifty percent of cutaneous melanomas are driven by activated BRAFV600E, but tumors treated with RAF inhibitors, even when they respond dramatically, rapidly adapt and develop resistance. Thus, there is a pressing need to identify the major mechanisms of intrinsic and adaptive resistance and develop drug combinations that target these resistance mechanisms. In a combinatorial drug screen on a panel of 12 treatment-naïve BRAFV600E mutant melanoma cell lines of varying levels of resistance to MAPK pathway inhibition we identified the combination PLX4720, a targeted inhibitor of mutated BRaf, and lapatinib, an inhibitor of the ERBB family of receptor tyrosine kinases, as synergistically cytotoxic in the subset of cell lines that displayed the most resistance to PLX4720. To identify potential mechanisms of resistance to PLX4720 treatment and synergy with lapatinib treatment we performed a multi-platform functional genomics analysis to profile the genome as well as the transcriptional and proteomic responses of these cell lines to treatment with PLX4720. We found modest levels of resistance correlated with the zygosity of the BRAF V600E allele and RTK mutational status. Layered over base-line resistance was substantial upregulation of many ERBB pathway genes in response to BRaf inhibition, thus generating the vulnerability to combination with lapatinib. The transcriptional responses of ERBB pathway genes are associated with a number of transcription factors, including ETS2 and its associated cofactors that represent a convergent regulatory mechanism conferring synergistic drug susceptibility in the context of diverse mutational landscapes. 12 BRAF mutant melanomas and 4 melanomas with WT BRAF were exposed plx4720 treatment to evaluate their responses after 8 hours of treatment. 5 of the 12 BRAF mutant melanomas responses were also evaluated in response to the treatment of lapatinib alone, masitinib alone, the combination of lapatinib with plx4720, or the combination of masitinib with plx4720. All samples were run in at least triplicate.

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Predominance of MAPK reactivation in early resistance to debrafenib/trametinib combination therapy of BRAF mutant metastatic melanoma.

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