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

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 which osimertinib induces c-Myc degradation. 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 osimertinib resistance. Our results also suggest a novel strategy to target c-Myc via disrupting the MKK3/c-Myc interaction to overcome osimertinib acquired resistance.