EGFR-mediated reactivation of MAPK signaling induces acquired resistance to GSK2118436 in BRAF V600E-Mutant NSCLC cell lines

Sung Moo Kim, Hwan Kim, Kang Won Jang, Min Hwan Kim, Jinyoung Sohn, Mi Ran Yun, Han Na Kang, Chan Woo Kang, Hye Ryun Kim, Sun Min Lim, Yong Wha Moon, Joo Hang Kim, Soonmyung Paik, Byoung Chul Cho

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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.

Original languageEnglish
Pages (from-to)1627-1636
Number of pages10
JournalMolecular Cancer Therapeutics
Volume15
Issue number7
DOIs
Publication statusPublished - 2016 Jul

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kim, S. M., Kim, H., Jang, K. W., Kim, M. H., Sohn, J., Yun, M. R., Kang, H. N., Kang, C. W., Kim, H. R., Lim, S. M., Moon, Y. W., Kim, J. H., Paik, S., & Cho, B. C. (2016). EGFR-mediated reactivation of MAPK signaling induces acquired resistance to GSK2118436 in BRAF V600E-Mutant NSCLC cell lines. Molecular Cancer Therapeutics, 15(7), 1627-1636. https://doi.org/10.1158/1535-7163.MCT-15-0375