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Updated: Jan 10, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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Combination therapy overcomes secondary PARPi resistance in ATM-deficient prostate cancer

Sara Arce-Gallego1, Victor Esquefa1, Heura Domenech2,3

  • 1Prostate Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.

NPJ Precision Oncology
|November 26, 2025
PubMed

Insights

PARP inhibitors (PARPi) show promise for metastatic prostate cancer (mPC) with HRR defects. Combining PARPi with ATR inhibitors (ATRi) can overcome resistance by enhancing replication stress, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • PARP inhibitors (PARPi) are effective for metastatic prostate cancer (mPC) with homologous recombination repair (HRR) defects.
  • The role of ATM defects in PARPi response and resistance mechanisms remains unclear.
  • Understanding resistance is crucial for improving treatment efficacy in mPC.

Purpose of the Study:

  • To investigate the mechanisms of acquired PARPi resistance in prostate cancer.
  • To explore the interplay between ATM-ATR signaling and PARPi sensitivity.
  • To identify novel therapeutic strategies to overcome PARPi resistance.

Main Methods:

  • Generated in vitro models of acquired PARPi resistance to olaparib and saruparib.
  • Performed functional characterization and drug sensitivity studies.
  • Evaluated the efficacy of combining PARPi with ATR inhibitors (ATRi) in vivo.

Main Results:

  • Resistant models bypassed G2/M arrest and showed increased reliance on the ATR-CHK1 axis for DNA damage and replication stress response.
  • Combining PARPi and ATRi restored sensitivity in resistant models by enhancing replication stress.
  • ATM-ATR signaling plays a key role in PARPi sensitivity in ATM-deficient mPC.

Conclusions:

  • Acquired resistance to PARPi involves a shift towards ATR-dependent pathways.
  • The combination of PARPi and ATRi is a promising strategy to overcome resistance in mPC.
  • Targeting ATM-ATR signaling may improve treatment outcomes for patients with mPC.

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