Adaptive resistance to dual BRAF/MEK inhibition in BRAF-driven tumors through autocrine FGFR pathway activation Journal Article
| Authors: | Wang, V. E.; Xue, J. Y.; Frederick, D. T.; Cao, Y.; Lin, E.; Wilson, C.; Urisman, A.; Carbone, D. P.; Flaherty, K. T.; Bernards, R.; Lito, P.; Settleman, J.; McCormick, F. |
| Article Title: | Adaptive resistance to dual BRAF/MEK inhibition in BRAF-driven tumors through autocrine FGFR pathway activation |
| Abstract: | 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. ©2019 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 23 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-12-01 |
| Start Page: | 7202 |
| End Page: | 7217 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-18-2779 |
| PUBMED: | 31515463 |
| PROVIDER: | scopus |
| PMCID: | PMC6891193 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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