Related Experiment Video
Updated: Jun 5, 2025
Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
Published on: February 24, 2023
Distinct effects of sacituzumab govitecan and berzosertib on DNA damage response in ovarian cancer
Jayakumar R Nair1, Tzu-Ting Huang1, Anu Sunkara1
1Women's Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.
Abstract:
Antibody-drug conjugates (ADCs) have become an important class of anticancer drugs in solid tumors including drug-resistant gynecologic malignancies. TROP2 is a cell surface antigen that is highly expressed in ovarian carcinoma (OC) but minimally expressed in normal ovarian tissues. In this study, we aimed to identify how TROP2-specific ADC, sacituzumab govitecan (SG), modulates DNA damage response pathways in drug-resistant OC. We found that SG induces G2/M arrest, increases RPA1 foci, and decreases replication fork speed, resulting in replication stress in TROP2-positive cells while these were less evident in TROP2-negative cells. In OC in vitro and in vivo models, SN-38 sensitivity and TROP2 expression play key roles in response to either ATR inhibitor or SG alone, or in combination. Additionally, inhibition of translesion DNA synthesis enhances SG and PARP inhibitor (PARPi) sensitivity in PARPi-resistant OC cells. These findings provide mechanistic insights for clinical development of SG in drug-resistant OC.
Insights
Sacituzumab govitecan (SG) induces DNA damage and replication stress in TROP2-positive ovarian cancer cells. Combining SG with other therapies may overcome resistance in gynecologic malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Antibody-drug conjugates (ADCs) are crucial in treating solid tumors, including resistant gynecologic cancers.
- TROP2 is a promising target, highly expressed in ovarian carcinoma (OC) but not in normal ovarian tissues.
Purpose of the Study:
- To investigate how the TROP2-specific ADC, sacituzumab govitecan (SG), affects DNA damage response pathways in drug-resistant OC.
- To understand the mechanisms underlying SG's efficacy and potential resistance in OC.
Main Methods:
- Utilized in vitro and in vivo OC models.
- Assessed DNA damage response pathways, including RPA1 foci and replication fork speed.
- Investigated the role of TROP2 expression and SN-38 sensitivity in treatment response.
Main Results:
- SG induced G2/M arrest and replication stress in TROP2-positive OC cells.
- TROP2 expression and SN-38 sensitivity were critical for response to SG and ATR inhibitors.
- Inhibiting translesion DNA synthesis enhanced sensitivity to SG and PARP inhibitors in resistant OC cells.
Conclusions:
- SG modulates DNA damage response pathways, leading to replication stress in TROP2-positive OC.
- Findings offer mechanistic insights for the clinical application of SG in drug-resistant OC.
- Combination strategies involving SG may overcome treatment resistance in OC.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:49Cancer Therapies
However, cancer treatments can pose several challenges, as therapies used to kill cancer cells are generally also toxic to normal cells. Moreover, cancer cells mutate rapidly and can develop resistance to chemical agents or radiation therapy. Besides, all types of cancer cells may not respond to the same therapy. Some cancer cells respond to one...