In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 7 ( 2016-07-01), p. 1627-1636
Abstract:
Although treatment of BRAF V600E–mutant non–small cell lung cancer (NSCLCV600E) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLCV600E, we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLCV600E to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR–RAS–CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF–CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo. Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLCV600E with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627–36. ©2016 AACR.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.MCT-15-0375
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2062135-8
SSG:
12
