MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer
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.
Authors
- Gouji Toyokawa (ORCID: https://orcid.org/0000-0002-6313-1169)
- Hideko Isozaki (ORCID: https://orcid.org/0000-0003-0124-996X)
- Kazuki Takada (ORCID: https://orcid.org/0000-0001-6377-9291)
- Atrayee Bhattacharya (ORCID: https://orcid.org/0000-0002-3322-6175)
- Tomoharu Yoshizumi (ORCID: https://orcid.org/0000-0002-4497-1816)
- Keisuke Shigeta (ORCID: https://orcid.org/0000-0002-9405-9446)
- Chie Kikutake (ORCID: https://orcid.org/0000-0002-9571-641X)
- Naoki Haratake
- Mikita Suyama (ORCID: https://orcid.org/0000-0001-9526-3193)
- Masafumi Yamaguchi (ORCID: https://orcid.org/0000-0002-0369-324X)
- Donald Küfe (ORCID: https://orcid.org/0000-0001-5743-8888)
- Tomoyoshi Takenaka (ORCID: https://orcid.org/0000-0002-0278-1854)
- Shinkichi Takamori (ORCID: https://orcid.org/0000-0001-8175-6798)
- Hiroki Ozawa (ORCID: https://orcid.org/0000-0002-3771-7940)
- Ayako Nakashoji (ORCID: https://orcid.org/0000-0003-2443-6995)
- Aaron N. Hata (ORCID: https://orcid.org/0000-0002-6127-318X)
- Asato Hashinokuchi
- Mototsugu Shimokawa
- Yuichi Yamada
- Kenichi Taguchi (ORCID: https://orcid.org/0000-0002-6753-2795)
Institutions
- Kyushu University (JP)
- Harvard University (US)
- Yamaguchi University (JP)
- Oita University (JP)
- Massachusetts General Hospital (US)
- National Hospital Organization Kyushu Cancer Center (JP)
- Dana-Farber Cancer Institute (US)
- Ono Clinic (JP)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41392-025-02482-7
- Citations
- 2
- Primary Topic
- Lung Cancer Treatments and Mutations
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- National Institutes of Health
- National Cancer Institute