Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

• DOI: 10.1016/j.celrep.2014.02.045
• Publication Date: 2014-03-27T12:33:14Z
• Authors: 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. Beije...; Federica Di Nicol...; Alberto Bardelli; Livio Trusolino; Rene Bernards
• Keywords: ERBB3; Kinome; ErbB

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 ERBB3 receptor tyrosine kinase sensitizes KRAS lung and colon cancer cells to MEK inhibitors. We show inhibition results in MYC-dependent transcriptional upregulation ERBB3, which is responsible intrinsic drug resistance. Drugs targeting both EGFR ERBB2, each capable forming heterodimers can reverse unresponsiveness by decreasing inhibitory phosphorylation proapoptotic proteins BAD BIM. Moreover, protein level biomarker response combinatorial treatment. These data suggest combination strategy treating cancers way identify tumors most likely benefit from such