Abstract 6906: c-Myc inhibition through targeting MMK3 and c-Myc interaction overcomes acquired resistance to third generation EGFR inhibitors in the treatment of EGFR mutant lung cancer

Abstract There is an urgent need to develop effective strategies for overcoming the inevitable acquired resistance to third generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib, which are approved for the treatment of advanced non-small cell lung cancer (NSCLC) harboring mutant EGFR. Our previous study has demonstrated c-Myc inhibition as a critical mechanism in mediating the therapeutic efficacy of osimertinib against EGFR mutant (EGFRm) NSCLCs/tumors and targeting c-Myc as an effective strategy for overcoming osimertinib acquired resistance. However, lack of specific c-Myc inhibitors restricts the application of this strategy in battling against acquired resistance to third generation EGFR-TKIs. Recently, we developed a novel strategy to inhibit c-Myc via disrupting the interaction of MKK3 and c-Myc, which stabilizes c-Myc protein. In this study, we found that the specific inhibitor of MKK3/c-Myc interaction, SGI-1027, effectively decreased c-Myc levels via disrupting the interaction and promoting c-Myc degradation in different osimertinib-resistant EGFRm NSCLC cell lines that possessed elevated levels of both c-Myc and MKK3 and increased interaction of MKK3 and c-Myc. SGI-1027, but not a p38 (that activates MKK3) or MKK3 kinase inhibitor, when combined with osimertinib or another third generation EGFR-TKI, synergistically decreased the survival of osimertinib-resistant EGFRm NSCLC cells with enhanced induction of apoptosis. In agreement, genetic knockdown of MKK3 led to c-Myc reduction and re-sensitized osimertinib-resistant EGFRm NSCLC cell lines to undergo apoptotic cell death upon osimertinib treatment. Moreover, the combination of SGI-1027 and osimertinib was also significantly more active than either single agent in suppressing the growth of osimertinib-resistant EGFRm NSCLC tumors in mice, indicating enhanced tumor-inhibitory effect in vivo. In sensitive EGFRm NSCLC cell lines, osimertinib effectively inhibited MKK3 and c-Myc interaction accompanied with substantial reduction of c-Myc levels, suggesting a critical mechanism by which osimertinib decreases c-Myc levels through promoting c-Myc degradation via disrupting MKK3 and c-Myc interaction. Hence, our findings reveal molecular mechanisms accounting for c-Myc reduction by osimertinib in sensitive EGFRm NSCLC cells and c-Myc elevation in EGFRm NSCLC with acquired resistance; it also suggests a novel strategy to target c-Myc via disrupting MKK3 and c-Myc interaction for overcoming acquired resistance and rationale for developing cancer therapeutic agents that specifically disrupts MKK3 and c-Myc interaction. (This study was supported by NIH/NCI R01 CA245386, UG1 CA233259, U01 CA168449, U01 CA217875, lung cancer SPORE P50CA217691 and Emory Winship Cancer Institute lung cancer research internal funds) Citation Format: Zhen Chen, Karin A Vallega, Dongsheng Wang, Haian Fu, Suresh S Ramalingam, Andrey A Ivanov, Shi-Yong Sun. c-Myc inhibition through targeting MMK3 and c-Myc interaction overcomes acquired resistance to third generation EGFR inhibitors in the treatment of EGFR mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6906.