Mitochondrial Morphology Dynamics Remodel Metabolism and Affect TKI Sensitivity in EGFR ‐Mutated Lung Cancer

ABSTRACT

EGFR‐mutant non‐small cell lung cancer patients often exhibit resistance to TKI therapy. This treatment resistance is a key factor affecting the efficacy of TKIs and a major bottleneck in cancer treatment. The potential underlying cause may be closely related to tumor cell metabolic reprogramming. In this study, we established an EGFR‐mutant lung cancer mouse model, isolating and culturing tumor primary cells to explore the cellular and molecular mechanisms of EGFR‐mutant lung cancer. Using techniques such as super‐resolution microscopy and RNA‐seq, we qualitatively and quantitatively analyzed the morphological changes of mitochondria within tumor cells following TKI treatment. Our results indicate that mitochondrial dynamics are remodeled toward increased mitochondrial fission during the early phase of TKI treatment. Furthermore, pharmacological inhibition of mitochondrial fission further sensitizes tumor cells to EGFR‐TKIs. Additionally, disrupting oxidative phosphorylation metabolism can increase the sensitivity of tumor cells to TKI treatment and reverse tumor cell resistance to TKI. Overall, these findings suggest that the metabolic reprogramming of mitochondrial OXPHOS in tumor cells mediates energy stress adaptation, altering their response to TKI treatment and providing new metabolic therapeutic targets to overcome EGFR‐TKI resistance.