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Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer

Mia Hofstad1,2, Andrea Woods3, Karla Parra3

  • 1Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA. mia.hofstad@utsouthwestern.edu.

Oncogene
|March 22, 2025
PubMed

Insights

Targeting DNA repair pathways in prostate cancer is crucial. Dual inhibition of ATR and DNA-PKcs kinases effectively radiosensitizes ATM-deficient castration resistant prostate cancer (CRPC) cells, offering a potential new therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mutations in the ataxia telangiectasia mutated (ATM) gene are frequent in advanced castration-resistant prostate cancer (CRPC).
  • Current therapies like poly(ADP-ribose) polymerase inhibitors show limited efficacy in ATM-mutant CRPC.
  • Alternative therapeutic strategies are urgently needed for ATM-deficient CRPC patients.

Purpose of the Study:

  • To investigate the DNA damage response (DDR) in ATM-deficient CRPC.
  • To identify alternative therapeutic targets for ATM-mutant CRPC.
  • To evaluate the efficacy of dual ATR and DNA-PKcs inhibition in ATM-deficient CRPC.

Main Methods:

  • Generation of matched ATM-proficient and ATM-deficient CRPC cell lines.
  • Unbiased phosphoproteomic screening to identify DDR pathway alterations.
  • In vitro and in vivo assessment of dual ATR/DNA-PKcs inhibition and Compound B in combination with irradiation.
  • Analysis of DNA damage markers (γH2AX) and replication fork dynamics.

Main Results:

  • ATM-deficient CRPC cells rely on ATR and DNA-PKcs activation for DNA repair.
  • Dual inhibition of ATR and DNA-PKcs effectively blocks DDR and radiosensitizes ATM-deficient CRPC.
  • RUVBL1/2 inhibitor Compound B degrades ATR and DNA-PKcs, radiosensitizing ATM-deficient CRPC in vitro and in vivo.
  • Dual inhibition impairs replication fork dynamics in ATM-deficient CRPC.

Conclusions:

  • ATM-deficient CRPC requires dual targeting of ATR and DNA-PKcs to inhibit DDR.
  • Compound B demonstrates potential as a novel radiosensitizing agent for ATM-deficient CRPC when combined with irradiation.
  • This strategy offers a promising therapeutic avenue for patients with ATM-mutant CRPC.

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