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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are frequent in advanced castration-resistant prostate cancer (CRPC).
• Current therapies like poly(ADP-ribose) polymerase inhibitors show limited efficacy in ATM-mutant CRPC patients.
• There is a critical need for novel therapeutic strategies targeting ATM-deficient CRPC.

Purpose of the Study:

• To investigate the impact of ATM loss on DNA damage response in CRPC.
• To identify alternative therapeutic targets and strategies for ATM-mutant CRPC.
• To evaluate the efficacy of dual ATR and DNA-PKcs inhibition in radiosensitizing ATM-deficient CRPC.

Main Methods:

• Generation of matched ATM-proficient and ATM-deficient CRPC cell lines.
• Unbiased phosphoproteomic screening to identify DDR pathway alterations.
• Treatment with ATR and DNA-PKcs inhibitors, individually and in combination.
• Assessment of γH2AX foci formation, replication fork dynamics, and radiosensitization.
• Evaluation of RUVBL1/2 ATPase inhibitor Compound B in vitro and in vivo.

Main Results:

• ATM-deficient CRPC cells rely on ATR and DNA-PKcs activation for DDR.
• Dual inhibition of ATR and DNA-PKcs effectively blocked γH2AX foci formation and radiosensitized ATM-deficient cells.
• Combined inhibition abrogated ATM pathway signaling and impaired replication fork dynamics.
• Compound B, a RUVBL1/2 inhibitor, degraded ATR and DNA-PKcs, radiosensitizing ATM-deficient CRPC in vitro and in vivo.

Conclusions:

• Dual targeting of ATR and DNA-PKcs is essential to inhibit DDR in ATM-deficient CRPC.
• Compound B demonstrates potential as a novel therapeutic agent for ATM-mutant CRPC when combined with irradiation.
• This study highlights a promising therapeutic avenue for a subset of prostate cancer patients with DDR deficiencies.