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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Synthetic lethality between ATR and POLA1 reveals a potential new target for individualized cancer therapy
Hanna Elisabeth Schneider1, Lisa-Maria Schmitt2, Albert Job2
1Center for Tumor Biology and Immunology, Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University Marburg, Marburg, Germany; Department of Medicine A - Hematology, Oncology and Pneumology, University Hospital Münster, Muenster, Germany.
Abstract:
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.
Insights
Synthetic lethality between ATR/CHK1 pathway and DNA polymerase POLA1 offers a new avenue for cancer treatment. ATR-deficient cells show increased sensitivity to POLA1 inhibitors, suggesting a targeted therapy approach.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The ATR-CHK1 pathway is crucial for DNA damage response and a key target in cancer therapy.
- Synthetic lethality between ATR inhibitors and DNA repair genes contributes to their anti-cancer effects.
- Previous research identified POLD1 and PRIM1 as potential synthetic lethal partners for ATR.
Purpose of the Study:
- To validate and characterize the synthetic lethality between ATR and DNA polymerase POLA1.
- To investigate the mechanisms underlying the sensitivity of ATR-deficient cells to POLA1 inhibition.
- To explore the potential of targeting the ATR/CHK1-POLA1 axis in cancer therapy.
Main Methods:
- Utilized ATR-deficient DLD-1 human colorectal cancer cells.
- Employed chemical inhibition of POLA1 and siRNA-mediated POLA1 depletion.
- Analyzed cell cycle and apoptotic markers using Flow cytometry (FACS) and Western blotting.
- Assessed sensitivity of various cancer cell lines to ATR/CHK1 inhibitors after POLA1 depletion.
Main Results:
- ATR-deficient cells exhibited increased sensitivity to POLA1 inhibitors, characterized by apoptosis and S phase arrest.
- siRNA-mediated POLA1 depletion in ATR-deficient cells mimicked chemical inhibition effects, confirming synthetic lethality.
- POLA1 depletion sensitized cancer cells to ATR and CHK1 inhibitors, indicating a reciprocal relationship.
- Confirmed synthetic lethality between ATR/CHK1 pathway and POLA1.
Conclusions:
- The synthetic lethality between ATR/CHK1 and POLA1 presents a promising strategy for personalized cancer therapy.
- POLA1 alterations can serve as a biomarker for sensitivity to ATR/CHK1 inhibitors.
- ATR-CHK1 pathway alterations may predict sensitivity to POLA1 inhibitors.
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