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
Authors: Zhen Chen, Karin A Vallega, Dongsheng Wang, Haian Fu, Suresh S Ramalingam, Andrey A Ivanov, Shi-Yong Sun
Journal: Cancer Research (2025)

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.