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

Yuanwang Pan, Han Han, Hai Hu, Hua Wang, Yueqiang Song, Yuan Hao, Xinyuan Tong, Ayushi S. Patel, Selim Misirlioglu, Sittinon Tang, Hsin Yi Huang, Ke Geng, Ting Chen, Angeliki Karatza, Fiona Sherman, Kristen E. Labbe, Fan Yang, Alison Chafitz, Chengwei Peng, Chenchen GuoAndre L. Moreira, Vamsidhar Velcheti, Sally C.M. Lau, Pengfei Sui, Haiquan Chen, J. Alan Diehl, Anil K. Rustgi, Adam J. Bass, John T. Poirier, Xiaoyang Zhang, Hongbin Ji*, Hua Zhang*, Kwok Kin Wong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)88-105.e8
JournalCancer cell
Volume41
Issue number1
DOIs
StatePublished - Jan 9 2023

Keywords

  • EGFR
  • ERBB2
  • KMT2D
  • SHP2
  • lung squamous cell carcinoma
  • organoids

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition'. Together they form a unique fingerprint.

Cite this