Targeting MKK3/c-Myc interaction to overcome osimertinib acquired resistance in EGFR mutant lung cancer

作者：Zhen Chen, Karin A. Vallega, Dongsheng Wang, Elsa Bildtsen, Haian Fu, Suresh S. Ramalingam, А. А. Иванов, Shi‐Yong Sun · 发表于：Cancer Letters · 年份：2025 · DOI：10.1016/j.canlet.2025.218010 · 被引用次数：4 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Mechanisms and Therapy、Cancer therapeutics and mechanisms

c-Myc inhibition is a critical mechanism in mediating the therapeutic efficacy of osimertinib against EGFR mutant (EGFRm) NSCLCs and accordingly targeting c-Myc is an effective strategy for overcoming osimertinib acquired resistance, a challenging issue in the clinic. However, lack of specific c-Myc inhibitors restricts the application of this strategy. The current study focused on determining the potential application of an alternative c-Myc inhibitory approach to overcome osimertinib acquired resistance via targeting the MKK3/c-Myc interaction that stabilizes c-Myc protein. SGI-1027, as the first disruptor of MKK3/c-Myc interaction, effectively decreased c-Myc levels via disrupting this 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 MKK3/c-Myc interaction. The combination of osimertinib with SGI-1027 synergistically decreased the survival of osimertinib-resistant cells and enhanced apoptosis. Consistently, MKK3 knockdown caused c-Myc reduction and sensitized osimertinib-resistant cells to undergo apoptosis upon osimertinib treatment. Moreover, the SGI-1027 and osimertinib combination was significantly more active than either single agent in suppressing the growth of osimertinib-resistant tumors in mice. In sensitive EGFRm NSCLC cell lines, osimertinib inhibited MKK3 and c-Myc interaction with reduction of c-Myc levels, suggesting a critical mechanism by...