Synthetic lethality between ATR and POLA1 reveals a potential new target for individualized cancer therapy

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2024-11, Vol.57, p.101038, Article 101038
• Main Authors: Schneider, Hanna Elisabeth, Schmitt, Lisa-Maria, Job, Albert, Lankat-Buttgereit, Brigitte, Gress, Thomas, Buchholz, Malte, Gallmeier, Eike
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis, Cancer therapy; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; ATR; Cell Line, Tumor; Cell Survival - drug effects; Checkpoint Kinase 1 - antagonists & inhibitors; Checkpoint Kinase 1 - genetics; Checkpoint Kinase 1 - metabolism; Colon cancer; DNA Damage; DNA Polymerase III - genetics; DNA Polymerase III - metabolism; Humans; Molecular Targeted Therapy; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Original Research; POLA1; Precision Medicine - methods; S phase arrest; Synthetic letality; Synthetic Lethal Mutations
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2024.101038

The ATR-CHK1 pathway plays a fundamental role in the DNA damage response and is therefore an attractive target in cancer therapy. The antitumorous effect of ATR inhibitors is at least partly caused by synthetic lethality between ATR and various DNA repair genes. In previous studies, we have identified members of the B-family DNA polymerases as potential lethal partner for ATR, i.e. POLD1 and PRIM1. In this study, we validated and characterized the synthetic lethality between ATR and POLA1. First, we applied a model of ATR-deficient DLD-1 human colorectal cancer cells to confirm synthetic lethality by using chemical POLA1 inhibition. Analyzing cell cycle and apoptotic markers via FACS and Western blotting, we were able to show that apoptosis and S phase arrest contributed to the increased sensitivity of ATR-deficient cancer cells towards POLA1 inhibitors. Importantly, siRNA-mediated POLA1 depletion in ATR-deficient cells caused similar effects in regard to impaired cell viability and cumulation of apoptotic markers, thus excluding toxic effects of chemical POLA1 inhibition. Conversely, we demonstrated that siRNA-mediated POLA1 depletion sensitized several cancer cell lines towards chemical inhibition of ATR and its main effector kinase CHK1. In conclusion, the synthetic lethality between ATR/CHK1 and POLA1 might represent a novel and promising approach for individualized cancer therapy: First, alterations of POLA1 could serve as a screening parameter for increased sensitivity towards ATR and CHK1 inhibitors. Second, alterations in the ATR-CHK1 pathway might predict in increased sensitivity towards POLA1 inhibitors. [Display omitted]