Abstract
High grade serous ovarian cancer (HGSOC) is a fatal gynecologic malignancy in the U.S. with limited treatment options. New therapeutic strategies include targeting of the cell cycle checkpoints, e.g., ATR and CHK1. We recently reported a promising clinical activity of the CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCA wild-type (BRCAwt) HGSOC patients. In this study, biopsies of treated patients and cell line models were used to investigate possible mechanisms of resistance to CHK1i. We report that BRCAwt HGSOC develops resistance to prexasertib monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death. On the other hand, we noted CHK1’s regulation on RAD51-mediated homologous recombination (HR) repair was not altered in CHK1i-resistant cells. Therefore, CHK1i sensitizes CHK1i-resistant cells to DNA damaging agents such as gemcitabine or hydroxyurea by inhibition of HR. In summary, our results demonstrate new mechanistic insights of functionally distinct CHK1 activities and highlight a potential combination treatment approach to overcome CHK1i resistance in BRCAwt HGSOC.
Highlights
High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the United States [1]
25% of HGSOC are deficient in homologous recombination (HR) DNA doublestrand break (DSB) repair due to BRCA1 and BRCA2 germline or somatic mutations [3, 4] sensitizing them to DNA damaging agents and PARP inhibitors (PARPis)
We previously reported that induction of nuclear RAD51 foci by PARPi olaparib was significantly attenuated by checkpoint kinase1 (CHK1) inhibitor (CHK1i) Prex in ovarian cancer cells, sensitizing BRCA wild-type (BRCAwt) HGSOC to PARPi via causing an HR-deficient phenotype [7]
Summary
High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy in the United States [1]. A majority of patients have no BRCA mutations and derive limited clinical benefit from PARPi monotherapy. A critical need remains for new effective therapeutic strategies for HGSOC without BRCA mutations and understanding resistance mechanisms associated with such treatments. We recently reported clinical activity of the CHK1 inhibitor (CHK1i) prexasertib (Prex) in recurrent BRCAwt HGSOC where half of heavily pretreated patients attained. We used tissue biopsies from HGSOC patients for subsequent transcriptome analysis and report the enrichment of genes of single-stranded DNA break (SSB) repair pathways in both CHK1i-resistant HGSOC cell lines and clinical samples. The HR regulatory activity plays an important role in combination therapy with DNA damaging agents highlighting the combination treatment strategies to overcome CHK1i resistance
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