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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / immunology
  • HEK293 Cells
  • Humans
  • Immunity, Innate / drug effects
  • Insulin-Like Growth Factor I / immunology
  • Insulin-Like Growth Factor I / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Transcription Factors
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Immunological
  • IGF1 protein, human
  • KRAS protein, human
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Insulin-Like Growth Factor I
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)