Abstract
Abstract Emergence of resistance is an invariable outcome in cancer progression that may involve memory of cancer cells to treatment. The oncogenic MUC1-C protein confers pleotropic resistance of cancer cells to diverse cytotoxic and targeted agents by unclear mechanisms. We demonstrate that MUC1-C regulates the interferon (IFN) type I/II pathways in H1975 non-small cell lung cancer (NSCLC) cells selected for osimertinib resistance (H1975-OR). Targeting MUC1-C in H1975-OR cells suppressed STAT1 and inflammatory IFN signaling in association with reversing the osimertinib-resistant phenotype. Studies of H1975-OR cells selected for growth in the absence of osimertinib demonstrate that revertant H1975-RT cells retain MUC1-C-dependent memory necessary for recalling osimertinib resistance. Mechanistically, osimertinib treatment of H1975-RT cells activates the MUC1 gene at a (i) promoter-like signature (PLS) by MUC1-C and STAT1, and (ii) proximal enhancer-like signature (pELS) by PBAF and JUN/AP-1. Targeting MUC1-C in osimertinib-treated H1975-RT and MGH170 NSCLC MET-amplified cells isolated from a patient refractory to osimertinib treatment suppressed induction of STAT1 and downstream IFN-stimulated genes (ISGs) encoding MX1, OAS1 and ISG15. Targeting MUC1-C, STAT1, PBRM1/PBAF and JUN/AP-1 further confirmed their dependencies for reemergence of osimertinib resistance in H1975-RT and MGH170 cells. In support of these results, high MUC1-C protein expression analyzed by IHC is associated with shorter progression free survival for patients treated with osimertinib. These findings and the demonstration that MUC1-C is upregulated in NSCLC cells from patients refractory to osimertinib indicate that MUC1-C drives osimertinib resistance in NSCLC cells by promoting an inflammatory memory response. Citation Format: Naoki Haratake, Atrayee Bhattacharya, Ayako Nakashoji, Hiroki Ozawa, Mototsugu Shimokawa, Donald Kufe. MUC1 is necessary for the inflammatory memory response to osimertinib resistance in NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3279.
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