Abstract 1209: FGFR inhibition re-sensitizes BRAF/MEK dual resistant cells to the BRAF/MEK inhibitor combination

Abstract The BRAF-MEK pathway is frequently mutated in human melanoma. Inhibitors of these kinases have proven to prolong survival in melanoma patients. However, clinical benefit is relatively short-lived due to acquired drug resistance. To explore mechanisms of resistance in melanoma cells treated with dual BRAF and MEK inhibitors, A375, a cell line harboring the BRAF V600E mutation, was treated with escalating doses of vemurafenib and cobimetinib to generate a cellular population resistant to combination therapy. These cells display a reversible resistance phenotype. Upon initial treatment of the drug combination, upregulation of pSTAT3 is observed but the cells lose dependency on the pSTAT3 pathway upon prolonged drug treatment. A pharmacological synthetic lethal screen was performed and the FGFR inhibitor class re-sensitizes the cells to BRAF and MEK inhibition through inhibitions of pERK. The dual resistant cells also displayed hyperactivation of the PI3K-AKT pathway. Interrogation of patient samples confirmed these findings. These findings provides a biological rationale for a polytherapy strategy using a FGFR inhibitor in patients with resistance to dual BRAF and MEK inhibition. <!–EndFragment–> Citation Format: Victoria E. Wang, Jeffrey Settleman, Frank McCormic. FGFR inhibition re-sensitizes BRAF/MEK dual resistant cells to the BRAF/MEK inhibitor combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1209. doi:10.1158/1538-7445.AM2017-1209