Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS

Shunsuke Kitajima, Hajime Asahina, Ting Chen, Sujuan Guo, Laura Gutierrez Quiceno, Jillian D. Cavanaugh, Ashley A. Merlino, Shoichiro Tange, Hideki Terai, Jong Wook Kim, Xiaoen Wang, Shan Zhou, Man Xu, Stephen Wang, Zehua Zhu, Tran C. Thai, Chiaki Takahashi, Yujin Wang, Richard Neve, Susanna StinsonPablo Tamayo, Hideo Watanabe, Paul T. Kirschmeier, Kwok Kin Wong, David A. Barbie

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)439-452.e6
JournalCancer Cell
Volume34
Issue number3
DOIs
Publication statusPublished - 2018 Sep 10
Externally publishedYes

Keywords

  • BET inhibitor
  • IL-6
  • innate immune signaling
  • KRAS
  • MEK inhibitor
  • non-small-cell lung cancer
  • STK11/LKB1
  • TBK1 inhibitor
  • TP53
  • YAP1 signaling

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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