What question did this study set out to answer?

The research aims to investigate ULK1 as a target to counteract autophagy-mediated resistance to chemotherapy in cancer cells.

April 5, 2026

Abstract 4667: Targeting ULK1 overcomes autophagy-mediated chemoresistance in cancer cell

Key Points

The research aims to investigate ULK1 as a target to counteract autophagy-mediated resistance to chemotherapy in cancer cells.
Targeted ULK1 inhibitors were developed and screened for their efficacy in blocking autophagic flux.
An LC3GFPmCherry tandem reporter was utilized to monitor autophagic activity.
Western blotting was performed to confirm on-target effects, such as decreased phosphorylated ATG13 and increased p62.
Combination treatments of ULK1 inhibitors with standard chemotherapeutics were applied across multiple cancer cell lines.
ULK1 inhibition led to increased cell death in cancer cells treated with chemotherapeutics.
The research identified a novel ULK1 inhibitor that effectively suppressed autophagy.
Targeting ULK1 reduced autophagic flux as indicated by the accumulation of p62.

Abstract

Abstract 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. Citation Format: Eun-Jung Kim, Youngjun Park. Targeting ULK1 overcomes autophagy-mediated chemoresistance in cancer cell abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4667.

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