Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived “TAK1 dependency signature” is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation.
► The TAK1 kinase promotes survival of KRAS-dependent colon cancer cells ► TAK1 dependency correlates with KRAS-mediated activation of Wnt signaling ► KRAS activates Wnt signaling via TAK1 in APC-deficient cancer cells ► KRAS upregulates BMP signaling, leading to increased TAK1 kinase activity
Present address: Department of Pharmacology and Experimental Therapeutics, Division of Medical Oncology and Hematology, Cancer Research Center, Boston University School of Medicine, Boston, MA 02118, USA
