Abstract
BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.
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Acknowledgements
This work is supported by Grants-in-Aid for Scientific Research (H. Ebi, 26830105 and 16K07164; S. Yano, 21390256) from Japan Society for the Promotion of Science, and Grant-in-Aid to Project for Cancer Research and Therapeutics Evolution (P-CREATE) from the Japan Agency for Medical Research and Development (H. Ebi and S.Yano, 16cm0106513h0001). A.C.F. is a George and Lavinia Blick Scholar and a Harrison Endowed Scholar in Cancer Research.
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Kotani, H., Adachi, Y., Kitai, H. et al. Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers. Oncogene 37, 1775–1787 (2018). https://doi.org/10.1038/s41388-017-0035-9
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DOI: https://doi.org/10.1038/s41388-017-0035-9
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