A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers

Area of Science:

• Molecular oncology
• DNA damage response
• Cancer genetics

Background:

• ATR is a key regulator of DNA repair and cell cycle checkpoints.
• ATR inhibition shows promise in cancer therapy, but genetic determinants of sensitivity are unclear.
• Synthetic lethality offers a strategy to selectively kill cancer cells by exploiting specific genetic vulnerabilities.

Purpose of the Study:

• To identify DNA repair genes that exhibit synthetic lethality with ATR deficiency in colorectal cancer cells.
• To investigate the functional interaction between ATR and POLD1 (DNA Polymerase Delta 1) in cancer cells.
• To explore the clinical potential of POLD1 mutations as biomarkers for ATR-targeted therapy.

Main Methods:

• A large-scale synthetic lethal screen using a DLD1 colorectal cancer cell line with ATR deficiency.
• Targeted knockdown of 288 DNA repair genes to identify synthetic lethal interactions.
• Pharmacological inhibition of ATR and CHK1 (Checkpoint Kinase 1) in POLD1-depleted cells.
• Assessment of apoptosis, cell cycle, DNA damage, and DNA repair capacity.

Main Results:

• A subset of DNA repair gene knockdowns selectively killed ATR-deficient cancer cells.
• A strong synthetic lethal interaction was identified between ATR and POLD1.
• Pharmacological ATR or CHK1 inhibition mimicked the synthetic lethality of POLD1 depletion in various colorectal cancer cell lines.
• POLD1 depletion in ATR-deficient cells led to apoptosis, increased DNA damage, and impaired DNA repair without cell cycle arrest.

Conclusions:

• POLD1 deficiency creates a vulnerability that can be exploited by inhibiting ATR or CHK1.
• POLD1 mutations, found in subsets of colorectal and endometrial cancers, may predict response to ATR/CHK1 inhibitors.
• This study provides a rationale for genotype-guided cancer therapy using ATR/CHK1 inhibitors.