Targeting ULK1 overcomes autophagy-mediated chemoresistance in cancer cell

Autophagy is a tightly regulated, lysosomedependent recycling process that preserves energy balance and proteostasis during stress, thereby promoting cell survival. Although chemotherapy aims to eliminate malignant cells, many tumors acquire resistance by engaging prosurvival autophagy. To disable this escape, we targeted Unc51like kinase 1 (ULK1), the initiator of autophagosome biogenesis. We generated a library by modifying reported ULK1 inhibitor scaffolds and screened for blockade of autophagic flux using an LC3GFPmCherry tandem reporter. Western blotting verified ontarget suppression, including phosphorylated ATG13 reduction and p62 accumulation, which nominated a novel lead compound. By treating this compound with standard chemotherapeutics in multiple cancer cell lines, cell death was increased concomitant with the blunted autophagic flux. These data support ULK1 as a tractable node to overcome autophagymediated chemoresistance and rationalize ULK1 inhibition as a combination strategy to deepen chemotherapy responses. Future study will evaluate antitumor efficacy and tolerability in vivo to advance a novel ULK1 inhibitor toward preclinical development.