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PARG inhibition in ATM-deficient prostate cancer: from mechanistic discovery to therapeutic potential

Xuan Zhou1,2, Chunyu Guo1, Zhiguo Fan1

  • 1Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China.

Journal of Translational Medicine
|May 7, 2026
PubMed
Abstract

Insights

Targeting poly (ADP-ribose) glycohydrolase (PARG) offers a new synthetic lethal strategy for ATM-deficient prostate cancer. PARG inhibition induces cell death by causing replication stress and DNA damage in these specific cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • ATM deficiency is common in castration-resistant prostate cancer (CRPC).
  • Therapeutic vulnerabilities in ATM-deficient prostate cancer are not well understood.
  • Identifying synthetic lethal strategies is crucial for targeting these cells.

Purpose of the Study:

  • To discover novel therapeutic vulnerabilities in ATM-deficient prostate cancer.
  • To identify small molecules selectively targeting ATM-deficient cancer cells.
  • To explore synthetic lethal strategies for precision oncology.

Main Methods:

  • Conducted unbiased small-molecule compound screening.
  • Validated candidate vulnerabilities in various prostate cancer cell lines with ATM manipulation.
  • Performed mechanistic studies on DNA damage, replication stress, and PARylation.
  • Evaluated in vivo efficacy in ATM-deficient xenograft models.

Main Results:

  • ATM-deficient prostate cancer cells showed sensitivity to poly (ADP-ribose) glycohydrolase (PARG) inhibition.
  • PARG inhibition led to replication-associated PARylation and severe replication stress in ATM-deficient cells.
  • This mechanism, distinct from classical PAR-dependent cell death, caused DNA double-strand breaks and cell death.
  • PARG inhibition suppressed tumor growth in vivo.

Conclusions:

  • Identified PARG inhibition as a synthetic lethal vulnerability in ATM-deficient prostate cancer.
  • Established a mechanistic link between ATM loss, ribonucleotide processing, and PARylation.
  • Supports clinical development of PARG inhibitors for ATM-deficient prostate cancer and other ATM-deficient malignancies.
Keywords:
ATM deficiencyCRPCPARGi

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