1. Academic Validation
  2. KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

  • Cancer Cell. 2022 Dec 7;S1535-6108(22)00562-1. doi: 10.1016/j.ccell.2022.11.015.
Yuanwang Pan 1 Han Han 1 Hai Hu 1 Hua Wang 2 Yueqiang Song 3 Yuan Hao 4 Xinyuan Tong 2 Ayushi S Patel 1 Selim Misirlioglu 1 Sittinon Tang 1 Hsin-Yi Huang 1 Ke Geng 1 Ting Chen 1 Angeliki Karatza 1 Fiona Sherman 1 Kristen E Labbe 1 Fan Yang 1 Alison Chafitz 1 Chengwei Peng 1 Chenchen Guo 2 Andre L Moreira 5 Vamsidhar Velcheti 1 Sally C M Lau 1 Pengfei Sui 2 Haiquan Chen 6 J Alan Diehl 7 Anil K Rustgi 8 Adam J Bass 8 John T Poirier 1 Xiaoyang Zhang 3 Hongbin Ji 9 Hua Zhang 10 Kwok-Kin Wong 11
Affiliations

Affiliations

  • 1 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  • 2 State 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.
  • 3 State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Laura 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.
  • 5 Department of Pathology, New York University School of Medicine, New York, NY, USA.
  • 6 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 7 Department of Biochemistry, Case Western Reserve University and Case Comprehensive Cancer Center, Cleveland, OH, USA.
  • 8 Herbert Irving Comprehensive Cancer Center, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • 9 State 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: [email protected]
  • 10 Laura 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: [email protected]
  • 11 Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA. Electronic address: [email protected]
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.

Keywords

EGFR; ERBB2; KMT2D; SHP2; lung squamous cell carcinoma; organoids.

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