This study contains 4 exomes of A375, parental, BRAF resistant population, MEK resistant population and a BRAF/MEK resistant population

Purpose:Combined mitogen-activated protein kinase (MAPK) pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAFV600Edriven tumors compared to either agent alone. However, resistance frequently arises. Experimental Design:We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacological synthetic lethal approach to identify a novel, adaptive resistance mechanism mediated through the fibroblast growth factor receptor (FGFR) pathway. Results:In response to drug treatment, transcriptional upregulation of FGF1 results in autocrine activation of FGFR, which sustains extracellular signal-regulated kinases (ERK) activation. FGFR inhibition overcomes resistance to dual BRAF/MEK inhibitors in both cell lines and patient derived xenograft (PDX) models. Abrogation of this bypass mechanism in the front-line setting enhances tumor killing and prevents the emergence of drug-resistant cells. Moreover, clinical data implicate serum FGF1 levels in disease prognosis. Conclusions:Taken together, these results describe a new, adaptive resistance mechanism that is more commonly observed in the context of dual BRAF/MEK blockade as opposed to single agent treatment and reveal the potential clinical utility of FGFR targeting agents in combination with BRAF and MEK inhibitors as a promising strategy to forestall resistance in a subset of BRAF-driven cancers.