KRAS serves as a key regulatory component in a signaling pathway that involves both upstream tyrosine kinase receptors and downstream effector pathways regulated by phosphatidylinositol 3-kinase (PI3K) and RAF. Activating mutations of the KRAS proto-oncogene are present in -30% lung adenocarcinomas and are among the most common oncogenic mutations in human cancers. Although both antibody and small molecule inhibitors of EGFR and PI3K show clinical benefit in subsets of lung cancer patients, tumors that harbor KRAS mutations have proven refractory to treatment, and no small molecule inhibitors of KRAS yet exist. Thus, identifying therapeutic strategies to target lung and other human cancers that harbor KRAS mutations remains an important unsolved problem and an area of tremendous clinical need. In recent work, we have used systematic functional genomic approaches to identify the serine threonine kinase TBK1 as a gene whose expression is essential for the survival of KRAS-driven non-small cell lung cancer (NSCLC) cell lines. TBK1 activates the NF-KB pathway and promotes the survival of KRAS dependent cell lines both in vitro and in vivo. These new observations not only identify a potentially druggable target that is essential for the survival of KRAS-driven cancers but also implicate the NF-KB pathway as a target for the subset of lung cancers that are dependent on KRAS. Based on these observations, this proposal focuses on testing whether TBKl and the NF-KB pathway are new actionable therapeutic targets in NSCLC.1Specifically, biochemical, genetic, and chemical biological approaches will be used (1) to identify TBK1 substrates necessary for the survival of KRAS-dependent tumors, (2) to develop small molecule inhibitors of TBK1, and (3) to investigate the role of NF-KB pathway in KRAS-dependent NSCLC. These studies will be performed in close collaboration with the other projects and cores of this Program. These studies will not only enhance our mechanistic understanding of this noncanonical IKK regulator but will also identify chemical compounds that will form the foundation for strategies to target this kinase therapeutically.
Lung cancers that harbor oncogenic mutations in the KRAS oncogene are refractory to both cytotoxic and targeted chemotherapy. This proposal focuses validating the NF-KB regulator TBK1 and NF-KB signaling as targets in KRAS-dependent lung cancers. These studies will not only provide insight into the biology of the NF-KB in lung cancer but will serve as a foundation for translational studies for the development of novel therapeutic agents.
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|Tan, Li; Gurbani, Deepak; Weisberg, Ellen L et al. (2017) Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorg Med Chem 25:1320-1328|
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