@article{4c7c8f09af194cc8ba236506c1787095,
title = "Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS",
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. Kitajima et al. identify BET-regulated YAP1 upregulation as a mediator of acquired and intrinsic resistance in KRAS;LKB1 and KRAS;TP53 mutant lung cancer cells, respectively, to combined TBK1 and MEK inhibition and show that intermittent BET inhibition overcomes this resistance.",
keywords = "BET inhibitor, IL-6, innate immune signaling, KRAS, MEK inhibitor, non-small-cell lung cancer, STK11/LKB1, TBK1 inhibitor, TP53, YAP1 signaling",
author = "Shunsuke Kitajima and Hajime Asahina and Ting Chen and Sujuan Guo and Quiceno, {Laura Gutierrez} and Cavanaugh, {Jillian D.} and Merlino, {Ashley A.} and Shoichiro Tange and Hideki Terai and Kim, {Jong Wook} and Xiaoen Wang and Shan Zhou and Man Xu and Stephen Wang and Zehua Zhu and Thai, {Tran C.} and Chiaki Takahashi and Yujin Wang and Richard Neve and Susanna Stinson and Pablo Tamayo and Hideo Watanabe and Kirschmeier, {Paul T.} and Wong, {Kwok Kin} and Barbie, {David A.}",
note = "Funding Information: We are grateful to Drs. P. Gao, M. Kim, H. Seav, H. Zhang, Y. Mitsuishi, K. Hinohara, and S. Masuda for providing materials, technical instruction, and useful discussion; and Molecular Biology Core Facilities at Dana-Farber Cancer Institute for the preparation and sequencing of RNA-seq and ChIP-seq. This work was supported by NCI-R01 CA190394-01 (D.A.B.); NCI P01 CA154303 (D.A.B.); the Gloria T. Maheu, Candice Bagby, and Heerwagen Family Funds for Lung Cancer Research (D.A.B.); NIH/NCI P01CA120964 (K.-K.W.), 5R01CA163896-04 (K.-K.W.), 5R01CA140594-07 (K.-K.W.), 5R01CA122794-10 (K.-K.W.), 5R01CA166480-04 (K.-K.W.); the Gross-Loh Family Fund for Lung Cancer Research (K.-K.W., D.A.B.); The Uehara Memorial Foundation Post-Doctoral Fellowship (S.K.); Strategic Young Researcher Overseas Visit Program for Accelerating Brain Circulation (S.K.); and JSPS Postdoctoral Fellowship For Research Abroad (S.K.). Additional support from a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research grant (SU2CAACR-DT1715). Stand Up to Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. Funding Information: We are grateful to Drs. P. Gao, M. Kim, H. Seav, H. Zhang, Y. Mitsuishi, K. Hinohara, and S. Masuda for providing materials, technical instruction, and useful discussion; and Molecular Biology Core Facilities at Dana-Farber Cancer Institute for the preparation and sequencing of RNA-seq and ChIP-seq. This work was supported by NCI- R01 CA190394-01 (D.A.B.); NCI P01 CA154303 (D.A.B.); the Gloria T. Maheu, Candice Bagby, and Heerwagen Family Funds for Lung Cancer Research (D.A.B.); NIH /NCI P01CA120964 (K.-K.W.), 5R01CA163896-04 (K.-K.W.), 5R01CA140594-07 (K.-K.W.), 5R01CA122794-10 (K.-K.W.), 5R01CA166480-04 (K.-K.W.); the Gross-Loh Family Fund for Lung Cancer Research (K.-K.W., D.A.B.); The Uehara Memorial Foundation Post-Doctoral Fellowship (S.K.); Strategic Young Researcher Overseas Visit Program for Accelerating Brain Circulation (S.K.); and JSPS Postdoctoral Fellowship For Research Abroad (S.K.). Additional support from a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research grant ( SU2CAACR-DT1715 ). Stand Up to Cancer is a program of the Entertainment Industry Foundation . Research grants are administered by the American Association for Cancer Research , the Scientific Partner of SU2C. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = sep,
day = "10",
doi = "10.1016/j.ccell.2018.08.009",
language = "English",
volume = "34",
pages = "439--452.e6",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}
