PT  - JOURNAL ARTICLE
AU  - Wang, Victoria E.
AU  - Xue, Jenny Y.
AU  - Frederick, Dennie T.
AU  - Cao, Yi
AU  - Lin, Eva
AU  - Wilson, Catherine
AU  - Urisman, Anatoly
AU  - Carbone, David P.
AU  - Flaherty, Keith T.
AU  - Bernards, Rene
AU  - Lito, Piro
AU  - Settleman, Jeff
AU  - McCormick, Frank
TI  - Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation
AID  - 10.1158/1078-0432.CCR-18-2779
DP  - 2019 Dec 01
TA  - Clinical Cancer Research
PG  - 7202--7217
VI  - 25
IP  - 23
4099  - http://clincancerres.aacrjournals.org/content/25/23/7202.short
4100  - http://clincancerres.aacrjournals.org/content/25/23/7202.full
SO  - Clin Cancer Res2019 Dec 01; 25
AB  - Purpose: Combined MAPK pathway inhibition using dual BRAF and MEK inhibitors has prolonged the duration of clinical response in patients with BRAFV600E-driven tumors compared with either agent alone. However, resistance frequently arises.Experimental Design: We generated cell lines resistant to dual BRAF/MEK inhibition and utilized a pharmacologic 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 potentiates 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 first-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.