This study reveals the key role of MUC1-C in conferring resistance to osimertinib in non-small cell lung cancer (NSCLC), demonstrating that its activation of the STAT1 and interferon signaling pathways establishes an inflammatory memory that maintains the drug-resistant phenotype. The study also shows that an antibody-drug conjugate targeting MUC1-C (M1C ADC) can effectively suppress resistant cells, offering a promising new therapeutic strategy.
Literature Overview
This article, titled 'MUCIN 1 confers inflammatory memory of tyrosine kinase inhibitor resistance in non-small cell lung cancer', was published in the journal Signal Transduction and Targeted Therapy. It presents a comprehensive review of a newly identified mechanism underlying resistance to osimertinib, a third-generation EGFR inhibitor, in non-small cell lung cancer (NSCLC). The study shows that the MUC1-C protein promotes resistance by regulating the STAT1 and IFN signaling pathways, and that this resistance exhibits characteristics of inflammatory memory, allowing cells to rapidly re-establish the resistant phenotype even after drug removal. Furthermore, the research validates the effectiveness of M1C ADC against drug-resistant cells, offering a novel therapeutic approach.
Background Knowledge
EGFR mutations are among the most common oncogenic drivers in NSCLC, and osimertinib, as a third-generation EGFR-TKI, is widely used to treat both EGFR-sensitive mutations and the T790M resistance mutation. However, prolonged use often leads to acquired resistance through various mechanisms, including MET amplification, EGFR C797S mutation, epithelial-mesenchymal transition (EMT), and compensatory pathway activation. MUC1, an evolutionarily conserved gene in mammals, encodes MUC1-C, a protein that under inflammatory conditions regulates cellular plasticity and participates in wound repair. However, persistent activation of MUC1-C in cancer cells promotes tumor progression and is associated with poor prognosis. This study employs multiple drug-resistant cell models to demonstrate the central role of MUC1-C in inflammatory memory and its potential as a therapeutic target.
Research Methods and Experiments
The research team established osimertinib-resistant cell models using H1975 and PC9 cell lines. They employed RNA-seq, GSEA, qPCR, and ChIP analyses to investigate the role of MUC1-C in drug resistance. Additionally, they silenced MUC1-C genetically or pharmacologically to determine whether the resistant phenotype could be reversed. Patient-derived resistant cells (e.g., MGH170 and MGH121) were also utilized to evaluate MUC1-C function in the context of MET amplification or dual EGFR mutations (T790M/C797S). The efficacy of M1C ADC against resistant tumors was further validated using patient-derived xenograft (PDX) models.
Key Conclusions and Perspectives
Research Significance and Prospects
This study highlights the significance of MUC1-C in NSCLC resistance, suggesting that targeting MUC1-C or its downstream enhancer domains may represent a promising approach to overcoming EGFR-TKI resistance. Furthermore, M1C ADC demonstrates potential as a therapeutic agent, warranting further clinical evaluation of its safety and efficacy.
Conclusion
This study systematically identifies MUC1-C as a critical mediator of EGFR-TKI resistance in NSCLC, maintaining a drug-resistant phenotype through activation of inflammatory memory pathways even after drug withdrawal. The MUC1 gene contains two enhancer-like domains (pELS-1 and pELS-2), activated by MUC1-C in combination with STAT1 or the MUC1-C/JUN/PBAF complex, which together orchestrate the establishment of inflammatory memory. These findings not only expand our understanding of resistance mechanisms in NSCLC but also provide new therapeutic targets for clinical intervention. Additionally, this research underscores the translational potential of M1C ADC for treating resistant tumors, suggesting its value in future clinical applications.
