Distinct effects of sacituzumab govitecan and berzosertib on DNA damage response in ovarian cancer
Jayakumar R. Nair,
Tzu-Ting Huang,
Anu Sunkara,
Margaret R. Pruitt,
Kristen R. Ibanez,
Chih-Yuan Chiang,
Ken Chih-Chien Cheng,
Kelli Wilson,
Thomas M. Cardillo,
Scott Hofsess,
Jung-Min Lee
Affiliations
Jayakumar R. Nair
Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA; Corresponding author
Tzu-Ting Huang
Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
Anu Sunkara
Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
Margaret R. Pruitt
Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
Kristen R. Ibanez
Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
Chih-Yuan Chiang
Functional Genomics Laboratory, National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA
Ken Chih-Chien Cheng
Functional Genomics Laboratory, National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA
Kelli Wilson
Functional Genomics Laboratory, National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA
Thomas M. Cardillo
Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA
Scott Hofsess
Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA
Jung-Min Lee
Women’s Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
Summary: 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.
