| Literature DB >> 30205046 |
Shunsuke Kitajima1, Hajime Asahina2, Ting Chen3, Sujuan Guo4, Laura Gutierrez Quiceno5, Jillian D Cavanaugh1, Ashley A Merlino1, Shoichiro Tange6, Hideki Terai1, Jong Wook Kim7, Xiaoen Wang4, Shan Zhou4, Man Xu4, Stephen Wang4, Zehua Zhu1, Tran C Thai1, Chiaki Takahashi8, Yujin Wang9, Richard Neve9, Susanna Stinson9, Pablo Tamayo10, Hideo Watanabe11, Paul T Kirschmeier4, Kwok-Kin Wong3, David A Barbie12.
Abstract
Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.Entities:
Keywords: BET inhibitor; IL-6; KRAS; MEK inhibitor; STK11/LKB1; TBK1 inhibitor; TP53; YAP1 signaling; innate immune signaling; non-small-cell lung cancer
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Year: 2018 PMID： 30205046 PMCID： PMC6422029 DOI： 10.1016/j.ccell.2018.08.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743