2. Academic Validation
  3. PARP inhibitor BMN673 triggers PARylation-mediated ATF4-GDF15 pathway to drive autophagy and ferroptosis in ataxia telangiectasia mutated gene-deficient colorectal cancer cells

PARP inhibitor BMN673 triggers PARylation-mediated ATF4-GDF15 pathway to drive autophagy and ferroptosis in ataxia telangiectasia mutated gene-deficient colorectal cancer cells

  • Mol Biomed. 2025 Nov 21;6(1):113. doi: 10.1186/s43556-025-00356-6.
Junqi Xiang # 1 2,  Jie Xu # 3,  Hui Fan # 1,  Qian Chen 1,  Yiting Lu 1,  Xinyan Wan 1,  Ying Jiang 1,  Xia Zhang 1,  Chundong Zhang 1,  Qingyuan Liu 4,  Degang Ding 5,  Yunlong Lei 6 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, P.R. China.
  • 2 Tianfu Jincheng Laboratory, Chengdu, 610093, China.
  • 3 The Center for Clinical Molecular Medical Detection, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 4 Department of Urology, Henan Provincial People's Hospital, Zhengzhou, 450003, China.
  • 5 Department of Urology, Henan Provincial People's Hospital, Zhengzhou, 450003, China. [email protected].
  • 6 Department of Biochemistry and Molecular Biology, and Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, P.R. China. [email protected].
  • 7 Tianfu Jincheng Laboratory, Chengdu, 610093, China. [email protected].
  • # Contributed equally.
PMID: 41266732 DOI: 10.1186/s43556-025-00356-6
Abstract

Colorectal Cancer (CRC) is a serious threat to human health, with an approximate 14% mutation rate in the ataxia telangiectasia-mutated (ATM) gene, which is involved in homologous recombination repair. BMN673 (talazoparib), a next-generation poly(ADP-ribose) polymerase (PARP) inhibitor, is the most potent PARP Inhibitor (PARPi) reported to date, demonstrating robust Anticancer activity. However, the precise mechanism underlying its action in ATM-deficient CRC remains unknown. This study demonstrated that BMN673 stimulated ATM-deficient CRC cell death via a synthetic lethal effect. RNA Sequencing analysis revealed significant enrichment of the PERK-ATF4 pathway, Mitophagy, and Ferroptosis. Functional assays confirmed that BMN673 induced a multifaceted cell death program comprising autophagy-associated death, Ferroptosis, and Mitophagy, in addition to synthetic lethal. Mechanistically, BMN673 was shown to enhance activating transcription factor 4 (ATF4) transcriptional activity by suppressing poly-ADP-ribosylation (PARylation), facilitating ATF4 binding to the Growth Differentiation Factor 15 (GDF15) promoter region and thereby inducing GDF15 transcriptional expression. Notably, GDF15 overexpression modulated the sensitivity of ATM-deficient CRC cells to BMN673 by promoting autophagy-associated cell death, Ferroptosis, and Mitophagy, contributing to the Anticancer effect of BMN673. Additionally, combining BMN673 with radiotherapy exerted a synergistic Anticancer effect on ATM-deficient CRC cells, which was prevented by Autophagy inhibition. The findings identified the ATF4-GDF15 pathway as a crucial mediator of BMN673 sensitivity in ATM-deficient CRC cells, revealing therapeutic vulnerability beyond canonical DNA damage repair pathways and providing new insight for combination therapy strategies.

Keywords

Colorectal cancer; Ferroptosis; GDF15; Mitophagy; PARP inhibitor BMN673.

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