TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer

Jonathan M. Cooper, Yi Hung Ou, Elizabeth A. McMillan, Rachel M. Vaden, Aubhishek Zaman, Brian O. Bodemann, Gurbani Makkar, Bruce A. Posner, Michael A. White

Research output: Contribution to journalArticle

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Abstract

Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiologic contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely dependent on TBK1-mediated support of AKT/mTORC1 pathway activation for survival.

Original languageEnglish (US)
Pages (from-to)5077-5094
Number of pages18
JournalCancer Research
Volume77
Issue number18
DOIs
StatePublished - Sep 15 2017

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Lung Neoplasms
Phosphotransferases
Neoplasms
Cell Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Cooper, J. M., Ou, Y. H., McMillan, E. A., Vaden, R. M., Zaman, A., Bodemann, B. O., ... White, M. A. (2017). TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. Cancer Research, 77(18), 5077-5094. https://doi.org/10.1158/0008-5472.CAN-17-0829

TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. / Cooper, Jonathan M.; Ou, Yi Hung; McMillan, Elizabeth A.; Vaden, Rachel M.; Zaman, Aubhishek; Bodemann, Brian O.; Makkar, Gurbani; Posner, Bruce A.; White, Michael A.

In: Cancer Research, Vol. 77, No. 18, 15.09.2017, p. 5077-5094.

Research output: Contribution to journalArticle

Cooper, JM, Ou, YH, McMillan, EA, Vaden, RM, Zaman, A, Bodemann, BO, Makkar, G, Posner, BA & White, MA 2017, 'TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer', Cancer Research, vol. 77, no. 18, pp. 5077-5094. https://doi.org/10.1158/0008-5472.CAN-17-0829
Cooper JM, Ou YH, McMillan EA, Vaden RM, Zaman A, Bodemann BO et al. TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. Cancer Research. 2017 Sep 15;77(18):5077-5094. https://doi.org/10.1158/0008-5472.CAN-17-0829
Cooper, Jonathan M. ; Ou, Yi Hung ; McMillan, Elizabeth A. ; Vaden, Rachel M. ; Zaman, Aubhishek ; Bodemann, Brian O. ; Makkar, Gurbani ; Posner, Bruce A. ; White, Michael A. / TBK1 provides context-selective support of the activated AKT/mTOR pathway in lung cancer. In: Cancer Research. 2017 ; Vol. 77, No. 18. pp. 5077-5094.
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