2. Academic Validation
  3. Targeting MKK3/c-Myc interaction to overcome osimertinib acquired resistance in EGFR mutant lung cancer

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

  • Cancer Lett. 2025 Aug 29:633:218010. doi: 10.1016/j.canlet.2025.218010.
Zhen Chen 1,  Karin A Vallega 1,  Dongsheng Wang 1,  Elsa Bildtsen 2,  Haian Fu 2,  Suresh S Ramalingam 1,  Andrey A Ivanov 2,  Shi-Yong Sun 3
Affiliations

Affiliations

  • 1 Departments of Hematology and Medical Oncology and Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
  • 2 Pharmacology and Chemical Biology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
  • 3 Departments of Hematology and Medical Oncology and Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA. Electronic address: ssun@emory.edu.
PMID: 40886822 DOI: 10.1016/j.canlet.2025.218010
Abstract

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.

Keywords

Acquired resistance; MKK3 and lung cancer; Osimertinib; c-Myc.

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