Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling

• DOI: 10.1158/0008-5472.can-14-0138-t
• Publication Date: 2014-04-19T02:23:44Z
• Authors: Marie Schoumacher; Kristen E. Hurov; Joseph Lehár; Yan Yan-Neale; Yuji Mishina; Dmitriy Sonkin; Joshua M. Korn; Daisy Flemming; Michael D. Jones; Brandon Antonakos; Vesselina G. Cooke; Janine Steiger; Jebediah Ledell; Mark D. Stump; William R. Sellers; Nika N. Danial; Wenlin Shao
• Keywords: Feedback, Physiological; 0301 basic medicine; Aniline Compounds; Morpholines; Aminopyridines; Mice, Nude; Drug Synergism; Pyrimidinones; MAP Kinase Kinase Kinases; 3. Good health; Proto-Oncogene Proteins p21(ras); Erlotinib Hydrochloride; Mice; 03 medical and health sciences; Cell Line, Tumor; Proto-Oncogene Proteins; Acetamides; Antineoplastic Combined Chemotherapy Protocols; Mutation; Animals; Humans; Female; Protein Kinase Inhibitors

Abstract Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism. Cancer Res; 74(12); 3294–305. ©2014 AACR.