ArticleCancer cell2018
Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.
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Article in Cancer cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52citing papers in PubMed
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Who cites it
52 citing papers in PubMed, 72 citations in OpenAlex.
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- Design and Synthesis of Novel Isoflavene TANK-Binding Kinase 1 Inhibitors With Anti-Inflammatory Activity.ChemMedChem · 2026Article
- Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer.Cancer cell · 2026Article
- PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer.Nature communications · 2026Article
- Dipeptidyl Peptidase 4 Restoration Facilitates Antitumor Immunity in KRAS-LKB1-Mutant Lung Cancer.Cancer research communications · 2025Article
- Targeting TAZ-TEAD in minimal residual disease enhances the duration of targeted therapy in melanoma models.Nature communications · 2025Article
- Suppression of STK11 induces expansion of polymorphonuclear myeloid-derived suppressive cells and activation of immune signaling in breast cancer.Cancer immunology, immunotherapy : CII · 2025Article
- The components and regulation of the Hippo pathway and its relationships with the progression and treatment of Non-small cell lung cancer (NSCLC).Cancer cell international · 2025Review
- Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.Cell reports. Medicine · 2025Article
- It's all downstream from here: RTK/Raf/MEK/ERK pathway resistance mechanisms in glioblastoma.Journal of neuro-oncology · 2025Review
- RNA sensing induced by chromosome missegregation augments anti-tumor immunity.Molecular cell · 2025Article
- YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis.JCI insight · 2024Article
- Progresses and Pitfalls of Epigenetics in Solid Tumors Clinical Trials.International journal of molecular sciences · 2024Review
- Developmental-status-aware transcriptional decomposition establishes a cell state panorama of human cancers.Genome medicine · 2024Article
- A review and perspective paper: Ras oncogene gets modest, from kingpin to mere henchman.Cellular and molecular life sciences : CMLS · 2024Review
- TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.Cancer discovery · 2024Article
- Mechanisms of resistance to targeted therapy and immunotherapy in non-small cell lung cancer: promising strategies to overcoming challenges.Frontiers in immunology · 2024Review
- Control of stem cell renewal and fate by YAP and TAZ.Nature reviews. Molecular cell biology · 2023Review
- Targeting the loss of cGAS/STING signaling in cancer.Cancer science · 2023Review
- Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma.Cancer research · 2023Article
Corrections and comments
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Authors and funding
25 authors at 8 institutions in 2 countries.
Shunsuke KitajimaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Hajime AsahinaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
Ting ChenDepartment 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.
Sujuan GuoDepartment 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.
Laura Gutierrez QuicenoPerlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.
Jillian D CavanaughDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Ashley A MerlinoDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Shoichiro TangeDepartment of Human Genetics, Graduate School of Biomedical Science, Tokushima University, Tokushima 770-8503, Japan.
Hideki TeraiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Jong Wook KimDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Xiaoen WangDepartment 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.
Shan ZhouDepartment 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.
Man XuDepartment 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.
Stephen WangDepartment 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.
Zehua ZhuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Tran C ThaiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Chiaki TakahashiDivision of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
Yujin WangGilead Sciences, Foster City, CA 94404, USA.
Richard NeveGilead Sciences, Foster City, CA 94404, USA.
Susanna StinsonGilead Sciences, Foster City, CA 94404, USA.
Pablo TamayoMoores Cancer Center and School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Hideo WatanabeTisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Paul T KirschmeierDepartment 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.
Kwok-Kin WongDepartment 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.
David A BarbieDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: dbarbie@partners.org.
Dana-Farber Cancer Institute · USGilead Sciences (United States) · USNYU Langone Health · USBroad Institute · USIcahn School of Medicine at Mount Sinai · USKanazawa University · JPTokushima University · JPUniversity of California, San Diego · US
Funding
Tuberous Sclerosis-Pathway and PathogenesisP01CA120964 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI David J. Kwiatkowski · 2007 to 2026
$35.9MStructureP01CA154303 · NCI · DANA-FARBER CANCER INST · PI JANNE, PASI A · 2012 to 2021
$17.8MMUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung CancerR01CA166480 · NCI · DANA-FARBER CANCER INST · PI KUFE, DONALD W., WONG, KWOK KIN · 2012 to 2021
$6.3MA Rational Systematic Approach to Find Combinations of Pharmacologic and Immune Therapies that Target Identifiable Oncogenic StatesU01CA217885 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI COHEN, EZRA, KAUFMAN, DAN S. · 2017 to 2021
$5.1MTherapeutic strategies for specific subsets of KRAS mutant lung cancersR01CA140594 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI WONG, KWOK KIN · 2009 to 2017
$4.5MTargeting the cytokine circuitry of KRAS-driven lung cancerR01CA190394 · NCI · DANA-FARBER CANCER INST · PI David A Barbie · 2015 to 2026
$4.5MMUC1-C is a Target for Reversing Immune Evasion and Resistance to ImmunotherapiesU01CA233084 · NCI · DANA-FARBER CANCER INST · PI KUFE, DONALD W., WONG, KWOK KIN · 2018 to 2022
$4.1MMechanisms of tumorigenesis in Brg1 mutant lung cancerR01CA216188 · NCI · BOSTON CHILDREN'S HOSPITAL · PI KIM, CARLA F., WONG, KWOK KIN · 2018 to 2022
$3.3MTherapeutic approaches for LKB1-deficient non-small cell lung cancerR01CA205150 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI HEYMACH, JOHN V., WONG, KWOK KIN · 2016 to 2020
$3.0MIn vivo analysis of EGFR mutant driven lung cancers responses to radiation therapR01CA122794 · NCI · DANA-FARBER CANCER INST · PI WONG, KWOK KIN · 2006 to 2015
$2.8MIn vivo murine models of metastasis for therapeutic testingR01CA163896 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SHARPLESS, NORMAN E, WONG, KWOK KIN · 2012 to 2016
$2.0MNCI NIH HHS P01 CA120964NCI NIH HHS P01 CA154303NCI NIH HHS R01 CA122794NCI NIH HHS R01 CA140594NCI NIH HHS R01 CA163896NCI NIH HHS R01 CA166480NCI NIH HHS R01 CA190394NCI NIH HHS R01 CA205150NCI NIH HHS R01 CA216188NCI NIH HHS U01 CA217885NCI NIH HHS U01 CA233084
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.
Indexed as
Adaptor Proteins, Signal TransducingAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsAntineoplastic Agents, ImmunologicalCarcinoma, Non-Small-Cell LungCell Line, TumorDisease Models, AnimalDrug Resistance, NeoplasmHEK293 CellsHumansImmunity, InnateInsulin-Like Growth Factor ILung NeoplasmsMiceMice, TransgenicAdaptor Proteins, Signal TransducingAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAntineoplastic Agents, ImmunologicalHras protein, mouseIGF1 protein, humanInsulin-Like Growth Factor IKRAS protein, humanMitogen-Activated Protein Kinase KinasesPhosphoproteinsProtein Kinase InhibitorsProtein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)STK11 protein, humanStk11 protein, mouseTranscription FactorsYAP1 protein, humanYAP-Signaling ProteinsBET inhibitorIL-6innate immune signalingKRASMEK inhibitornon-small-cell lung cancerSTK11/LKB1TBK1 inhibitorTP53YAP1 signaling
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