RT Journal Article
SR Electronic
T1 Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 7202
OP 7217
DO 10.1158/1078-0432.CCR-18-2779
VO 25
IS 23
A1 Wang, Victoria E.
A1 Xue, Jenny Y.
A1 Frederick, Dennie T.
A1 Cao, Yi
A1 Lin, Eva
A1 Wilson, Catherine
A1 Urisman, Anatoly
A1 Carbone, David P.
A1 Flaherty, Keith T.
A1 Bernards, Rene
A1 Lito, Piro
A1 Settleman, Jeff
A1 McCormick, Frank
YR 2019
UL http://clincancerres.aacrjournals.org/content/25/23/7202.abstract
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.