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
  • 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. [email protected].
  • 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. [email protected].
  • # 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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