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A proof-of-concept phase 2 study of the CHK1 inhibitor prexasertib with translational study outcomes in platinum-resistant recurrent, BRCA wild-type high-grade serous ovarian carcinoma

ABSTRACT: A proof-of-concept phase 2 study of the CHK1 inhibitor prexasertib with translational study outcomes in platinum-resistant recurrent, BRCA wild-type high-grade serous ovarian carcinoma

PROVIDER: PRJNA1049777 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27129714_1.fastq.gz	Fastqsanger.gz
	SRR27129714_2.fastq.gz	Fastqsanger.gz
	SRR27129715_1.fastq.gz	Fastqsanger.gz
	SRR27129715_2.fastq.gz	Fastqsanger.gz
	SRR27129716_1.fastq.gz	Fastqsanger.gz

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A proof-of-concept phase 2 study of the CHK1 inhibitor prexasertib with translational study outcomes in platinum-resistant recurrent, BRCA wild-type high-grade serous ovarian carcinoma

Project description:This proof-of-concept phase 2 trial (NCT02203513) evaluated the clinical activity of the CHK1 inhibitor (CHK1i), prexasertib, in platinum-resistant (PR) recurrent high-grade serous ovarian carcinoma (HGSOC) patients without BRCA mutation. The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. 49 heavily-pretreated patients were enrolled. Among the 39 RECISTv1.1-evaluable patients, ORR was 30.7%, the median PFS was 5.8 months. Toxicity was manageable. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3, MCM7) associated with lack of clinical benefit. Subsequent preclinical experiments demonstrated synthetic lethality of POLA1 inhibition in combination with CHK1i in PR-HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

2024-02-22 | GSE249587 | GEO

A pan-cancer transcriptome analysis to identify the molecular mechanism of prexasertib resistance_RNASeq

Project description:The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms which protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity. We included RNASseq data here as part of the study. Microarray data was uploaded separately.

2020-02-05 | GSE143152 | GEO

A pan-cancer transcriptome analysis to identify the molecular mechanism of prexasertib resistance [microarray]

Project description:The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms which protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity. We included microarray data here as part of the study. RNAseq data was uploaded separately.

2020-02-24 | GSE143007 | GEO

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

Project description:The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

| PRJNA1088759 | ENA

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

Project description:The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

| PRJNA1088758 | ENA

Characterization of resistance to prexasertib in ovarian cancer cell line OVCAR5

Project description:We developed a CHK1 inhibitor Prexasertib resistant strain of ovarian cancer cell line OVCAR5 in lab. This was used to compare transcriptome profiles to study changes in expression profiles of genes that might be involved with resistance. Total RNA was isolated from three replicate cultures of OVCAR5R (IC50 viability >3 micromolar Prexasertib) and 3 replicate cultures of parental OVCAR5 (IC50 viability=7.5nM) and then subjected to Hiseq4000 illumina RNA-seq analysis, with paired end sequencing. Data file contains CPM-TMM values after zoom normalization.

2020-05-02 | GSE149724 | GEO

RNA-seq profiling of A549 cells with sgRNA knockouts that confer prexasertib resistance

Project description:A549 cells with FOXM1 or LIN54 sgRNA knockout, which confers resistance to the CHK1 inhibitor prexasertib, were generated. These cells and control (empty vector) cells were synchronized in S phase, released for 1 hour and treated with 100 nM prexasertib or DMSO (vehicle) for 2 hours. RNA-seq profiling was performed to identify drug-induced perturbations in gene expression in these cells.

2021-02-24 | GSE154545 | GEO

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

Project description: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.

| S-EPMC7426265 | biostudies-literature

The selective RRM2 inhibitor TAS1553 is synergistic with multiple CHK1 inhibitors in neuroblastoma

Project description:Tumor cells experience high replication stress, driving genomic instability. Recent studies reveal that neuroblastoma, a pediatric tumor, heavily relies on the ATR-CHK1 signaling pathway. Our prior work identified RRM2, part of the ribonucleotide reductase (RNR) complex, as a key target in neuroblastoma. In this study, we assessed the effects of the RNR-disrupting compound TAS1553 on neuroblastoma cells. Both in vitro and in vivo, TAS1553 inhibited cell growth and triggered apoptosis. Additionally, TAS1553 synergized with CHK1 inhibitors prexasertib and SRA737, increasing replication stress and DNA damage. We also observed these effects in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Notably, TAS1553 downregulated RNA splicing factors, suggesting potential for combination therapies with splicing inhibitors.

2025-12-31 | GSE279147 | GEO

Mis-splicing of mitotic regulators sensitizes SF3B1-mutated human HSCs to CHK1 inhibition [scRNA-seq]

Project description:Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs remain unclear. Here, we identify the mis-splicing program in human HSCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis in single cell transcriptomics, critically BUBR1 and CDC27, leading to altered differentiation and delayed G2/M progression. Mutant SF3B1 mis-splicing or reduced expression of BUBR1 and CDC27 was sufficient to delay G2/M transit, leading to activation of CHK1, sensitizing cells to CHK1 inhibition. Clinical CHK1 inhibitor prexasertib selectively targeted SF3B1-mutant HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition.

2024-05-29 | GSE263300 | GEO

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