2. Academic Validation
  3. Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS

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

  • Cancer Cell. 2018 Sep 10;34(3):439-452.e6. doi: 10.1016/j.ccell.2018.08.009.
Shunsuke Kitajima 1,  Hajime Asahina 2,  Ting Chen 3,  Sujuan Guo 4,  Laura Gutierrez Quiceno 5,  Jillian D Cavanaugh 1,  Ashley A Merlino 1,  Shoichiro Tange 6,  Hideki Terai 1,  Jong Wook Kim 7,  Xiaoen Wang 4,  Shan Zhou 4,  Man Xu 4,  Stephen Wang 4,  Zehua Zhu 1,  Tran C Thai 1,  Chiaki Takahashi 8,  Yujin Wang 9,  Richard Neve 9,  Susanna Stinson 9,  Pablo Tamayo 10,  Hideo Watanabe 11,  Paul T Kirschmeier 4,  Kwok-Kin Wong 3,  David A Barbie 12
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
  • 6 Department of Human Genetics, Graduate School of Biomedical Science, Tokushima University, Tokushima 770-8503, Japan.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 8 Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
  • 9 Gilead Sciences, Foster City, CA 94404, USA.
  • 10 Moores Cancer Center and School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • 11 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 12 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: dbarbie@partners.org.
PMID: 30205046 DOI: 10.1016/j.ccell.2018.08.009
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.

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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