Adaptive Resistance to Dual BRAF/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation.
| Publication Type | Academic Article |
| Authors | Wang V, Xue J, Frederick D, Cao Y, Lin E, Wilson C, Urisman A, Carbone D, Flaherty K, Bernards R, Lito P, Settleman J, McCormick F |
| Journal | Clin Cancer Res |
| Volume | 25 |
| Issue | 23 |
| Pagination | 7202-7217 |
| Date Published | 09/12/2019 |
| ISSN | 1557-3265 |
| Keywords | Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, Fibroblast Growth Factor 1, MAP Kinase Kinase 1, Melanoma, Proto-Oncogene Proteins B-raf, Receptor, Fibroblast Growth Factor, Type 1 |
| 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. |
| DOI | 10.1158/1078-0432.CCR-18-2779 |
| PubMed ID | 31515463 |
| PubMed Central ID | PMC6891193 |