PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS -targeted therapy

Mitophagy, the selective degradation of mitochondria by lysosomes, is a major mitochondrial quality-control pathway, yet its role in lung cancer initiation and therapeutic response remains poorly understood. We investigated PINK1-dependent mitophagy in human lung adenocarcinoma and directly monitored mitophagy in vivo using mito-QC reporter mice during lung tumor development. We found that PINK1 activity and mitophagy are increased in human tumors and are activated from the earliest stages of tumorigenesis. Genetic inhibition of PINK1 impaired oncogenic transformation but had little impact once tumor cells were established, identifying mitophagy as a critical early adaptation during lung cancer initiation. PINK1 deficiency markedly enhanced the efficacy of KRAS -targeted therapy in vitro and in vivo. Together, our findings identify PINK1-dependent mitophagy as an early vulnerability in KRAS -driven lung cancer and provide a rationale for targeting mitophagy to improve the efficacy of KRAS -targeted therapies.