MUC1-C IS ESSENTIAL FOR INFLAMMATORY MEMORY OF TYROSINE KINASE INHIBITOR RESISTANCE IN NSCLC CELLS

This study identifies the oncogenic protein MUC1-C as a key driver of resistance to the EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancers (NSCLCs).MUC1-C promotes resistance by activating STAT1 and type I/II interferon pathways, creating an inflammatory memory of the resistant phenotype. This memory is maintained via MUC1-C/STAT1 interaction at one enhancer region (pELS-1) and MUC1-C/JUN/PBAF at another (pELS-2) in the MUC1 gene. MUC1-C also mediates resistance to combination EGFR/MET inhibitors and a fourth-generation EGFR TKI (TQB3804). Importantly, targeting MUC1-C with an antibody-drug conjugate (M1C ADC) is effective both in vitro and in a patient-derived xenograft model, making MUC1-C a promising therapeutic target for TKI-refractory NSCLC. Overall design: ATAC-seq for WT H1975 and revertant H1975 (H1975-RT) cells ( cells were treated with Osimertinib for 12 weeks to acquire resistance and then left untreated to make them sensitive to Osi) and ATAC seq for H1975-RT with Control guide RNA(csgRNA) and MUC1-C guide RNA (MUC1-CsgRNA).