Intrinsic resistance to MEK inhibition in kras mutant lung and colon cancer through transcriptional induction of ERBB3

Chong Sun, Sebastijan Hobor, Andrea Bertotti, Davide Zecchin, Sidong Huang, Francesco Galimi, Francesca Cottino, Anirudh Prahallad, Wipawadee Grernrum, Anna Tzani, Andreas Schlicker, Lodewyk F A Wessels, Egbert F. Smit, Erik Thunnissen, Pasi Halonen, Cor Lieftink, Roderick L. Beijersbergen, Federica DiNicolantonio, Alberto Bardelli, Livio TrusolinoRene Bernards

Research output: Contribution to journalArticle

Abstract

There are no effective therapies for the ~30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.

Original languageEnglish
Pages (from-to)86-93
Number of pages8
JournalCell Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Oct 4 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Sun, C., Hobor, S., Bertotti, A., Zecchin, D., Huang, S., Galimi, F., Cottino, F., Prahallad, A., Grernrum, W., Tzani, A., Schlicker, A., Wessels, L. F. A., Smit, E. F., Thunnissen, E., Halonen, P., Lieftink, C., Beijersbergen, R. L., DiNicolantonio, F., Bardelli, A., ... Bernards, R. (2014). Intrinsic resistance to MEK inhibition in kras mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Reports, 7(1), 86-93. https://doi.org/10.1016/j.celrep.2014.02.045