Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer

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.

MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

“…A total of 2.5 μM CDK1i was previously shown to partially rescue cell death after depletion of ATR by an inducible degron ( Eykelenboom et al, 2013 ), suggesting that this threshold of CDK1 activity also may be relevant for ATR inhibition as well. The MMB-FOXM1 target gene CCNB1 appears to be a key gene for CHK1i resistance, as it was identified as a significant hit in H460 cells and depletion of CCNB1 reduced CHK1i sensitivity in recently published work in ovarian cancer cells ( Nair et al, 2020 ). Cyclin B1 levels however were not predictive of CHK1i sensitivity in a panel of head and neck squamous cell lines ( van Harten et al, 2019 ), indicating that other components of the mitotic program may be involved in CHK1i sensitivity.…”

Predictive value of RAD51 on the survival and drug responsiveness of ovarian cancer

“…Under exposure to exogenous insults, formation of RAD51 foci in cell nucleus represents the assembly and initiation of DNA damage repair [ 18 ]. Recently, RAD51 was reported to be a reliable surrogate marker capable of predicting the capacity for homologous recombination repair [ 18 , 19 ].…”

A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515)

“…23 The limited tumor tissue available as preserved tumor tissue from only 19 of 29 patients precluded our ability to look for somatic mutations in genes such as CDK1/CyclinB1 and the DDR pathway that have been demonstrated to confer resistance to CHK1 inhibition. 24 Additionally, we are not aware of the mutational status of DDR genes in this patient cohort as germline sequencing was not within the scope of this study.…”