| Autor: |
Gupta, Nitasha, Huang, Tzu-Ting, Nair, Jayakumar R., An, Daniel, Zurcher, Grant, Lampert, Erika J., McCoy, Ann, Cimino-Mathews, Ashley, Swisher, Elizabeth M., Radke, Marc R., Lockwood, Christina M., Reichel, Jonathan B., Chiang, Chih-Yuan, Wilson, Kelli M., Cheng, Ken Chih-Chien, Nousome, Darryl, Lee, Jung-Min |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 6/21/2023, Vol. 15 Issue 701, p1-17, 17p |
| Abstrakt: |
Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork–related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC. Editor's summary: Poly (ADP-ribose) polymerase inhibitors (PARPis) are used to treat BRCA-mutant high-grade serous ovarian carcinoma (HGSC), but most patients develop resistance. Here, Gupta and colleagues used high-throughput drug screens to identify that checkpoint kinase 1 (CHK1) inhibitors were cytotoxic to PARPi-sensitive and -resistant BRCA-mutant HGSC in vitro and in mouse xenograft models. However, a phase 2 trial of the CHK1 inhibitor prexasertib in patients with BRCA-mutant HGSC yielded an objective response rate of 6%. A further exploratory analysis found that overexpression of genes associated with replication stress and fork stabilization, including Bloom syndrome RecQ helicase (BLM), were associated with clinical benefit. These findings suggest that BLM might serve as a biomarker for CHK1 inhibitor sensitivity in these patients. —Melissa Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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