TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers
Menée in vitro, cette étude suggère que l'inhibition de l'activité de la protéine kinase TAK1 pourrait être une stratégie thérapeutique pertinente pour les cancers du côlon réfractaires aux traitements actuels et présentant une signalisation KRAS et Wnt aberrante
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. º The TAK1 kinase promotes survival of KRAS-dependent colon cancer cells º TAK1 dependency correlates with KRAS-mediated activation of Wnt signaling º KRAS activates Wnt signaling via TAK1 in APC-deficient cancer cells º KRAS upregulates BMP signaling, leading to increased TAK1 kinase activity Profiling of colon cancer cells dependent on KRAS-mediated signaling defines a TAK1 dependency signature for stratifying heterogeneous patient populations. TAK1 inhibition may provide a potential therapeutic strategy for a treatment-refractory subset of colon cancers.