American Association for Cancer Research
10780432ccr182779-sup-207711_3_supp_5720620_pwc4fh.xlsx (70.98 kB)

Supplementary Data Table 4 from Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation

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posted on 2023-03-31, 21:01 authored by Victoria E. Wang, Jenny Y. Xue, Dennie T. Frederick, Yi Cao, Eva Lin, Catherine Wilson, Anatoly Urisman, David P. Carbone, Keith T. Flaherty, Rene Bernards, Piro Lito, Jeff Settleman, Frank McCormick

Table S4 shows the moleculared used in the pharmacological screen and the corresponding IC50 values


Damon Runyon Postdoctoral Award


LungCancer Research Foundation Fellowship

Department of Defense





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. 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. 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. 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.