2. Academic Validation
  3. KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition

KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition

  • Cell Death Differ. 2026 Jan 8. doi: 10.1038/s41418-025-01657-7.
Nana Chen # 1 2,  Mouxiang Fang # 1 3,  Leqi Zhong # 1,  Xiaolong Li 4,  Yijia Zhou 5,  Jianhua Zhan 1,  Manli Wang 6,  Zhaoyuan Fang 7,  Hua Wang 5,  Shijie Tang 8,  Fang Liu 1,  Bing Deng 1,  Ning Chen 1,  Jie Lei 1,  Yuchen Zhang 1,  Min Yan 1,  Zhengzhi Zou 3,  Yijun Gao 1,  Chong Chen 6,  Wenzhao Zhong 2,  Srinivas Vinod Saladi 9,  Hongbin Ji 10 11,  Quentin Liu 12 13,  Zifeng Wang 14,  Bin He 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Psychobehavioral Cancer Research Center, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2 Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 3 MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.
  • 4 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • 5 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.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
  • 7 Department of Colorectal Surgery and Oncology, the Second Affiliated Hospital, and Center for Biomedical Systems and Informatics, Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 8 Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 Department of Cell and Cancer Biology, University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA.
  • 10 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. [email protected].
  • 11 School of Medicine, Westlake University, Hangzhou, China. [email protected].
  • 12 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Psychobehavioral Cancer Research Center, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 13 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. [email protected].
  • 14 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Psychobehavioral Cancer Research Center, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 15 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Psychobehavioral Cancer Research Center, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41507359 DOI: 10.1038/s41418-025-01657-7
Abstract

Lineage plasticity in non-small cell lung Cancer (NSCLC) drives resistance to tyrosine kinase inhibitor (TKI) therapies, yet the epigenetic drivers of this phenotypic transition remain poorly defined. Here, we identify loss of the Histone Methyltransferase KMT2D as a critical event that disrupts adenocarcinoma lineage fidelity and promotes squamous transition. KMT2D expression is markedly reduced in TKI-resistant NSCLC with squamous-like features, and its mutation correlates with elevated squamous lineage markers and poorer clinical outcomes. Mechanistically, KMT2D loss triggers global transcriptional and epigenomic reprogramming, upregulating squamous master regulators such as ΔNp63 and SOX2. CRISPR-based screening reveals that KMT2D-deficient tumors are preferentially dependent on AURKA to maintain squamous identity and cell proliferation. Notably, loss of KMT2D enhances AURKA stability and activity by disrupting its interaction with the E3 Ligase FBXW7, resulting in reduced ubiquitination and prolonged AURKA signaling. Pharmacologic inhibition of AURKA abrogates squamous features and suppresses tumor growth in patient-derived organoids, xenografts, and orthotopic models, with KMT2D-deficient tumors exhibiting heightened sensitivity. These findings uncover that KMT2D alteration drives chromatin reprogramming that facilitates adeno-to-squamous transition and identifies AURKA as a lineage-specific vulnerability, providing a precision strategy to overcome TKI resistance.Statement of significanceOur study identifies KMT2D loss as a key event of lineage switch that promotes adeno-to-squamous transition and TKI resistance in NSCLC. This epigenetic shift renders tumors dependent on AURKA, revealing a novel therapeutic target to counteract drug resistance and improve treatment outcomes.

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