ArticleCancer cell2023
KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.
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Article in Cancer cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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65citing papers in PubMed
6.5field-weighted citation impact, top 2% of its field
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Who cites it
65 citing papers in PubMed, 85 citations in OpenAlex.
- Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial.Signal transduction and targeted therapy · 2024Trial
- Epigenetics in lung cancer precision medicine: from bench to bedside-a narrative review.Translational lung cancer research · 2026Review
- Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition.The Journal of clinical investigation · 2026Article
- KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition.Cell death and differentiation · 2026Article
- Histone methyltransferase KMT2D promotes castration-resistant prostate cancer progression by reactivating AR through FOXA1.Oncogene · 2026Article
- Paeoniflorin inhibits colorectal cancer stem cell properties via regulating LINC01711/KMT2D/KLF7 axis.Journal of gastrointestinal oncology · 2026Article
- Leukemia inhibitory factor drives malignant progression in lung squamous cell carcinoma via the PI3K/AKT/GSK-3β/β-catenin axis.Journal of molecular histology · 2026Article
- Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.Nature reviews. Cancer · 2026Review
- Application of organoid models in basic and translational research of lung cancer: a narrative review.Translational lung cancer research · 2026Review
- Integrating machine learning and single-cell sequencing to reveal the role of kinase-related genes in subtype classification and prognostic significance of lung squamous cell carcinoma.Discover oncology · 2026Article
- Integration Analysis of Bayesian and Machine Learning for Heterogeneity, Biomarkers, and Optimal Combination Regimens of Pucotenlimab in Solid Tumors.Cancer medicine · 2026Article
- Prognostic comparison of ablation and laser excision in a population-based cohort of stage III-IV pulmonary malignant tumors.Journal of cardiothoracic surgery · 2026Article
- Review
- Expanding the Anatomical Distribution of PRRX1::KMT2D Fusion Mesenchymal Neoplasms: A Rare Mediastinal Case Report.Cancer reports (Hoboken, N.J.) · 2026Article
- A multi-dimensional omics framework identifies GPR35 as a driver of M2 macrophage activation and poor prognosis in colorectal cancer.Frontiers in immunology · 2026Article
- A 7-gene expression signature predicts immune microenvironment remodeling and neoadjuvant chemo-immunotherapy response in lung squamous cell carcinoma.Frontiers in immunology · 2026Article
- A pathway-informed mutual exclusivity framework to detect genetic interactions in pediatric cancer.BMC medical genomics · 2025Article
- Cancer Genomic Alterations and Microenvironmental Features Encode Synergistic Interactions with Disease Outcomes.Molecular cancer research : MCR · 2025Article
- Targeting SHP2 to reverse immune evasion and resistance to anti-PD-1 therapy in non-small cell lung cancer.Cell communication and signaling : CCS · 2025Article
- B lymphocytes and tertiary lymphoid structures have a prognostic impact on penile squamous cell carcinoma.The journal of pathology. Clinical research · 2025Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
33 authors at 9 institutions in 2 countries.
Yuanwang PanLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Han HanLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Hai HuLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Hua WangState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Yueqiang SongState Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
Yuan HaoLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Applied Bioinformatics Laboratories, Office of Science and Research, New York University Grossman School of Medicine, New York, NY, USA.
Xinyuan TongState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Ayushi S PatelLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Selim MisirliogluLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Sittinon TangLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Hsin-Yi HuangLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Ke GengLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Ting ChenLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Angeliki KaratzaLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Fiona ShermanLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Kristen E LabbeLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Fan YangLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Alison ChafitzLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Chengwei PengLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Chenchen GuoState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Andre L MoreiraDepartment of Pathology, New York University School of Medicine, New York, NY, USA.
Vamsidhar VelchetiLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Sally C M LauLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Pengfei SuiState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Haiquan ChenDepartment of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
J Alan DiehlDepartment of Biochemistry, Case Western Reserve University and Case Comprehensive Cancer Center, Cleveland, OH, USA.
Anil K RustgiHerbert Irving Comprehensive Cancer Center, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
Adam J BassHerbert Irving Comprehensive Cancer Center, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
John T PoirierLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
Xiaoyang ZhangState Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
Hongbin JiState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: hbji@sibcb.ac.cn.
Hua ZhangLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA; Hillman Cancer Center, UPMC, Pittsburgh, PA 15232, USA; Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: huz59@pitt.edu.
Kwok-Kin WongLaura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. Electronic address: kwok-kin.wong@nyulangone.org.
NYU Langone Health · USChinese Academy of Sciences · CNColumbia University · USFudan University · CNCase Comprehensive Cancer CenterFudan University Shanghai Cancer Center · CNNew York University · USOffice of Science · USUniversity of Pittsburgh · US
Funding
Tumor Biology and Microenvironment ProgramP30CA013696 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI Anil K Rustgi · 1985 to 2026
$115.3MVaccine FacilityP30CA016087 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ANIRBAN MAITRA · 1985 to 2026
$83.1MTransformed Esophageal Epithelial Cells and the Tumor MicroenvironmentP01CA098101 · NCI · UNIVERSITY OF PENNSYLVANIA · PI RUSTGI, ANIL K · 2003 to 2023
$31.7MTR&D 4: Revealing Microstructure: Biophysical modeling and validation for discovery and clinical careP41EB017183 · NIBIB · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI Christopher M Collins · 2014 to 2026
$19.3MStructureP01CA154303 · NCI · DANA-FARBER CANCER INST · PI MEYERSON, MATTHEW L. · 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
$6.3MMUC1-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
$4.1MResponse and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung CancerR01CA248896 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI NEEL, BENJAMIN G., WONG, KWOK KIN · 2021 to 2025
$3.4MTargeting novel therapeutic vulnerabilities in LKB1 mutant tumors.R01CA219670 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI EL-BARDEESY, NABEEL, WONG, KWOK KIN · 2018 to 2022
$3.4MMechanisms 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
$3.0MNCI NIH HHS P01 CA098101NCI NIH HHS P01 CA154303NCI NIH HHS P30 CA013696NCI NIH HHS P30 CA016087NCI NIH HHS R01 CA166480NCI NIH HHS R01 CA205150NCI NIH HHS R01 CA216188NCI NIH HHS R01 CA219670NCI NIH HHS R01 CA248896NCI NIH HHS U01 CA233084NIBIB NIH HHS P41 EB017183
Abstract
Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.
Indexed as
Carcinoma, Non-Small-Cell LungCarcinoma, Squamous CellLung NeoplasmsAnimalsCarcinogenesisCell Transformation, NeoplasticDNA-Binding ProteinsHumansLungMiceNeoplasm ProteinsProtein-Tyrosine Kinasesras ProteinsDNA-Binding ProteinsKMT2D protein, humanNeoplasm ProteinsProtein-Tyrosine Kinasesras ProteinsEGFRERBB2KMT2Dlung squamous cell carcinomaorganoidsSHP2
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