Approximately 50% of epithelial ovarian cancers (EOC) exhibit defective DNA repair via homologous recombination (HR) due to genetic and epigenetic alterations of HR pathway genes. Defective HR is an ...important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors, which exhibit synthetic lethality when applied to HR-deficient cells. Here, we describe the genotypic and phenotypic characteristics of HR-deficient EOCs, discuss current and emerging approaches for targeting these tumors, and present challenges associated with these approaches, focusing on development and overcoming resistance.
Defective DNA repair via HR is a pivotal vulnerability of EOC, particularly of the high-grade serous histologic subtype. Targeting defective HR offers the unique opportunity of exploiting molecular differences between tumor and normal cells, thereby inducing cancer-specific synthetic lethality; the promise and challenges of these approaches in ovarian cancer are discussed in this review.
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the ...interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies.
Targeting replication stress in cancer therapy da Costa, Alexandre André B A; Chowdhury, Dipanjan; Shapiro, Geoffrey I ...
Nature reviews. Drug discovery,
01/2023, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the ...DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, polyADP-ribosepolymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.
To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus.
A literature search and prospectively ...defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence.
The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs.
All women diagnosed with epithelial ovarian cancer should have germline genetic testing for
and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic
variant, somatic tumor testing for
pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in
genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.
Homologous recombination DNA repair deficiency (HRD) is a functional defect in homologous recombination DNA repair, arising from germline or somatic mutations in BRCA1/2 or other mechanisms. Cells ...with HRD are more sensitive to platinum and poly(ADP-ribose) polymerase inhibitors (PARPi). HRD generates permanent changes in the genome with specific, quantifiable patterns (“genomic scars”). Clinical tests for HRD, such as the Myriad genomic instability score and Foundation Medicine loss of heterozygosity test, aim to predict the presence of HRD based on genomic features. Clinical trials of PARPi in ovarian cancer have evaluated genetic mutations and HRD genomic assays as potential biomarkers of response. Patients with HRD due to BRCA1/2 mutations are more likely to respond to PARPi than those with wild-type (WT) BRCA1/2. In some clinical trials, patients with WT BRCA1/2 who were predicted to be HRD by a genomic test exhibited greater clinical benefit from PARPi than patients with WT BRCA1/2 and no evidence of HRD. HRD tests therefore hold promise as predictive biomarkers for PARPi and other DNA-damaging agents. However, HRD tests vary in terms of the specific genomic features they measure, and the methods used to determine thresholds defining patients with HRD. Also, HRD test results and PARPi responses can be discordant: for instance, tumors with reversion mutations that restore HR function still exhibit a “genomic scar” of HRD, and PARPi resistance mechanisms independent of HR can result in lack of PARPi response despite HRD. Emerging methods to predict HRD, including genomic and functional assays, may overcome some of these challenges. Evaluation of HRD in the clinical setting is an important tool that has potential to aid patient selection for PARPi and other DNA-damaging agents in ovarian cancer, but understanding the details of these tests and their limitations is critical to ensure their optimal clinical application.
•Homologous recombination DNA repair deficiency (HRD) is a functional defect in homologous recombination DNA repair.•Clinical tests for HRD detect “genomic scars” caused by HRD, which are permanent regardless of changes in HR function.•In trials of PARP inhibitors (PARPi), patients whose cancers have HRD by clinical tests may have more benefit from PARPi.•Clinical tests for HRD have limitations and discordance can occur between HRD test results and clinical responses to PARPi.•Genomic tests for HRD are potential biomarkers for PARPi and other DNA-damaging drugs, but more research is needed.
Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end ...resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication ...forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease. Low EZH2 levels reduce H3K27 methylation, prevent MUS81 recruitment at stalled forks and cause fork stabilization. As a consequence, loss of function of the EZH2/MUS81 axis promotes PARPi resistance in BRCA2-deficient cells. Accordingly, low EZH2 or MUS81 expression levels predict chemoresistance and poor outcome in patients with BRCA2-mutated tumours. Moreover, inhibition of Ezh2 in a murine Brca2
breast tumour model is associated with acquired PARPi resistance. Our findings identify EZH2 as a critical regulator of genomic stability at stalled forks that couples histone modifications to nuclease recruitment. Our data identify EZH2 expression as a biomarker of BRCA2-deficient tumour response to chemotherapy.
Uterine serous carcinoma (USC) is a distinct histologic subtype of endometrial cancer, with molecular characteristics suggesting frequent cell-cycle dysregulation paired with a high level of ...oncogene-driven replication stress. Adavosertib is a potent and selective oral inhibitor of the WEE1 kinase, a key regulator of the G2/M and S phase cell-cycle checkpoints. Because cells with impaired cell-cycle regulation and high replication stress may be vulnerable to WEE1 inhibition, we conducted this study to assess the activity of adavosertib monotherapy in women with recurrent USC.
This was a single-arm two-stage phase II study with coprimary end points of objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6). Women with recurrent USC were treated with adavosertib monotherapy at a starting dose of 300 mg orally once daily days 1 through 5 and 8 through 12 of a 21-day cycle until disease progression.
In 34 evaluable patients, 10 total responses (one confirmed complete response, eight confirmed partial responses, and one unconfirmed partial response) were observed with adavosertib monotherapy, for an ORR of 29.4% (95% CI, 15.1 to 47.5). Sixteen patients were progression-free at 6 months, for a PFS6 rate of 47.1% (95% CI, 29.8 to 64.9). Median PFS was 6.1 months, and median duration of response was 9.0 months. Frequent treatment-related adverse events (AEs) included diarrhea (76.5%), fatigue (64.7%), nausea (61.8%), and hematologic AEs. No clear correlation of clinical activity with specific molecular alterations was observed in an exploratory biomarker analysis.
Adavosertib monotherapy demonstrated encouraging and durable evidence of activity in women with USC, and further investigation of this agent in this cancer and biomarkers of activity are indicated.
PARP inhibitors have transformed treatment for ovarian cancer, a cancer notable for homologous recombination (HR) deficiencies and aberrant DNA repair, especially in the high-grade serous subtype. ...PARP inhibitors are now approved for recurrent ovarian cancer as maintenance following response to platinum chemotherapy and
-mutated (
m) cancer treatment.
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