Guiding ATR and PARP inhibitor combinationswith chemogenomic screens

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells by targeting DNA repair pathways.
• However, the tolerability of these drug combinations is often limited by hematological toxicities.

Purpose of the Study:

• To identify genetic alterations that sensitize cancer cells to combined ATRi and PARPi treatment, aiming to improve efficacy and reduce toxicity.
• To elucidate the underlying mechanisms of this hypersensitivity and optimize dosing strategies.

Main Methods:

• A genome-wide CRISPR-Cas9 screen was employed to identify genetic vulnerabilities.
• Specific genetic alterations investigated include RNase H2 deficiency, RAD51 paralog mutations, and the alternative lengthening of telomeres (ALT) mechanism.
• Cellular responses and in vivo dosing schedules were evaluated.

Main Results:

• The study identified specific genetic alterations, such as RNase H2 deficiency, that confer hypersensitivity to combined ATRi (RP-3500) and PARPi treatment.
• These combinations demonstrate potent anti-tumor activity at sub-therapeutic doses when used as single agents in cells with these genetic alterations.
• A detailed mechanism of hypersensitivity in RNase H2-deficient cells was uncovered, revealing an irreversible replication catastrophe.

Conclusions:

• The findings provide a comprehensive dataset and an experimental framework for developing more tolerable and efficacious ATRi and PARPi combination therapies.
• Targeting specific genetic vulnerabilities can enhance the therapeutic window of combined DNA repair inhibitor strategies.
• This approach offers a promising strategy for precision oncology, applicable to other drug combination studies.