TAK1 Inhibition Promotes Apoptosis in KRAS-dependent Colon Cancers

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Feb 21

PMID 22341439

Citations 176

Authors

Anurag Singh

Michael F Sweeney

Min Yu

Alexa Burger

Patricia Greninger

Cyril Benes

Daniel A Haber

Jeff Settleman

Affiliations

Soon will be listed here.

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.

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References

Haber D, Gray N, Baselga J . The evolving war on cancer. Cell. 2011; 145(1):19-24. DOI: 10.1016/j.cell.2011.03.026. View

Sekiya T, Adachi S, Kohu K, Yamada T, Higuchi O, Furukawa Y . Identification of BMP and activin membrane-bound inhibitor (BAMBI), an inhibitor of transforming growth factor-beta signaling, as a target of the beta-catenin pathway in colorectal tumor cells. J Biol Chem. 2003; 279(8):6840-6. DOI: 10.1074/jbc.M310876200. View

Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F . Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009; 6(9):519-27. DOI: 10.1038/nrclinonc.2009.111. View

Melisi D, Xia Q, Paradiso G, Ling J, Moccia T, Carbone C . Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst. 2011; 103(15):1190-204. PMC: 3149044. DOI: 10.1093/jnci/djr243. View

Moffat J, Grueneberg D, Yang X, Kim S, Kloepfer A, Hinkle G . A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell. 2006; 124(6):1283-98. DOI: 10.1016/j.cell.2006.01.040. View

Campeau E, Ruhl V, Rodier F, Smith C, Rahmberg B, Fuss J . A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS One. 2009; 4(8):e6529. PMC: 2717805. DOI: 10.1371/journal.pone.0006529. View

Lin Z, Gao C, Ning Y, He X, Wu W, Chen Y . The pseudoreceptor BMP and activin membrane-bound inhibitor positively modulates Wnt/beta-catenin signaling. J Biol Chem. 2008; 283(48):33053-8. PMC: 2662247. DOI: 10.1074/jbc.M804039200. View

Barbie D, Tamayo P, Boehm J, Kim S, Moody S, Dunn I . Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009; 462(7269):108-12. PMC: 2783335. DOI: 10.1038/nature08460. View

Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U . Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol. 2002; 22(4):1184-93. PMC: 134640. DOI: 10.1128/MCB.22.4.1184-1193.2002. View

10.

Behrens J, von Kries J, Kuhl M, Bruhn L, Wedlich D, Grosschedl R . Functional interaction of beta-catenin with the transcription factor LEF-1. Nature. 1996; 382(6592):638-42. DOI: 10.1038/382638a0. View

11.

Bolstad B, Irizarry R, Astrand M, Speed T . A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 2003; 19(2):185-93. DOI: 10.1093/bioinformatics/19.2.185. View

12.

Rawlins P, Mander T, Sadeghi R, Hill S, GAMMON G, Foxwell B . Inhibition of endotoxin-induced TNF-alpha production in macrophages by 5Z-7-oxo-zeaenol and other fungal resorcylic acid lactones. Int J Immunopharmacol. 1999; 21(12):799-814. DOI: 10.1016/s0192-0561(99)00047-8. View

13.

Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N . A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009; 15(6):489-500. PMC: 2743093. DOI: 10.1016/j.ccr.2009.03.022. View

14.

Ebi H, Corcoran R, Singh A, Chen Z, Song Y, Lifshits E . Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest. 2011; 121(11):4311-21. PMC: 3204842. DOI: 10.1172/JCI57909. View

15.

Meylan E, Dooley A, Feldser D, Shen L, Turk E, OuYang C . Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature. 2009; 462(7269):104-7. PMC: 2780341. DOI: 10.1038/nature08462. View

16.

Janssen K, Alberici P, Fsihi H, Gaspar C, Breukel C, Franken P . APC and oncogenic KRAS are synergistic in enhancing Wnt signaling in intestinal tumor formation and progression. Gastroenterology. 2006; 131(4):1096-109. DOI: 10.1053/j.gastro.2006.08.011. View

17.

Downward J . Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003; 3(1):11-22. DOI: 10.1038/nrc969. View

18.

Nakamura K, Kim S, Ishidate T, Bei Y, Pang K, Shirayama M . Wnt signaling drives WRM-1/beta-catenin asymmetries in early C. elegans embryos. Genes Dev. 2005; 19(15):1749-54. PMC: 1182335. DOI: 10.1101/gad.1323705. View

19.

Phelps R, Chidester S, Dehghanizadeh S, Phelps J, Sandoval I, Rai K . A two-step model for colon adenoma initiation and progression caused by APC loss. Cell. 2009; 137(4):623-34. PMC: 2706149. DOI: 10.1016/j.cell.2009.02.037. View

20.

Reid J, Gariboldi M, Sokolova V, Capobianco P, Lampis A, Perrone F . Integrative approach for prioritizing cancer genes in sporadic colon cancer. Genes Chromosomes Cancer. 2009; 48(11):953-62. DOI: 10.1002/gcc.20697. View