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 Stinson; Pablo Tamayo; Hideo Watanabe; Paul T Kirschmeier; Kwok-Kin Wong; David A Barbie

doi:10.1016/j.ccell.2018.08.009

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.

Authors

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

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.

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)

Abstract

Publication types

MeSH terms

Substances

Grants and funding