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<p>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&#xa0;revealed significant enrichment of the PERK-ATF4 pathway, mitophagy, and ferroptosis. Functional assays&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Junqi Xiang,
  • Jie Xu,
  • Hui Fan,
  • Qian Chen,
  • Yiting Lu,
  • Xinyan Wan,
  • Ying Jiang,
  • Xia Zhang,
  • Chundong Zhang,
  • Qingyuan Liu,
  • Degang Ding,
  • Yunlong Lei

摘要

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.