title: TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.forename: Michael F
authors.initials: MF
authors.lastname: Sweeney
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Alexa
authors.initials: A
authors.lastname: Burger
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005856:Germ-Free Life; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D015398:Signal Transduction; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D019485:Bone Morphogenetic Proteins; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C099510:TAB1 protein, MAPKKK activator, vertebrate; D051176:beta Catenin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins