2. Academic Validation
  3. MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer

MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer

  • Signal Transduct Target Ther. 2025 Nov 28;10(1):389. doi: 10.1038/s41392-025-02482-7.
Shinkichi Takamori # 1,  Naoki Haratake # 1 2,  Atrayee Bhattacharya # 3,  Chie Kikutake 4,  Hiroki Ozawa 1,  Keisuke Shigeta 1,  Ayako Nakashoji 1,  Hideko Isozaki 5,  Mototsugu Shimokawa 6,  Mikita Suyama 4,  Asato Hashinokuchi 7,  Kazuki Takada 8,  Gouji Toyokawa 8,  Yuichi Yamada 9,  Tomoyoshi Takenaka 8,  Kenichi Taguchi 10,  Masafumi Yamaguchi 7,  Tomoharu Yoshizumi 8,  Aaron N Hata 5,  Donald Kufe 11
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Yufu, Oita, Japan.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Atrayee_Bhattacharya@dfci.harvard.edu.
  • 4 Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  • 5 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan.
  • 7 Department of Thoracic Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan.
  • 8 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 9 Fukuoka Pathology Clinic, Fukuoka, Japan.
  • 10 Cancer Pathology Laboratory, NHO Kyushu Cancer Center, Fukuoka, Japan.
  • 11 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Donald_Kufe@dfci.harvard.edu.
  • # Contributed equally.
PMID: 41309558 DOI: 10.1038/s41392-025-02482-7
Abstract

Resistance of NSCLCs to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), is mediated by pleotropic mechanisms that pose a significant challenge for subsequent treatment. We report that the oncogenic MUC1-C/M1C protein confers resistance to osimertinib by regulating the STAT1 and interferon (IFN) type I/II pathways. Studies of osimertinib-resistant NSCLC cell lines selected for growth in the absence of drug demonstrate dependence on MUC1-C and the STAT1 pathway for memory of the refractory phenotype. This inflammatory memory of TKI resistance is mediated through activation of the MUC1 gene at (i) a proximal enhancer-like signature 1 (pELS-1) by MUC1-C and STAT1 and (ii) a pELS-2 by MUC1-C, JUN/AP-1, and PBAF. Our results further reveal that the MUC1-C-driven STAT1 inflammatory response promotes resistance of patient-derived (i) EGFR mutant NSCLC cells with MET amplification to the combination of osimertinib+MET TKIs, and (ii) EGFR(T790M/C797S) NSCLC cells to the 4th generation EGFR TKI TQB3804. Of clinical significance, we report that NSCLC cells dependent on MUC1-C for TKI resistance are druggable with an antibody-drug conjugate (M1C ADC) in vitro and in a PDX tumor model. These findings demonstrate that MUC1-C (i) is essential for TKI resistance of NSCLC cells by driving an inflammatory memory response and (ii) is a target for M1C ADC treatment of TKI-refractory NSCLCs.

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