scholarly journals Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Vera L. Silva ◽  
Jayeta Saxena ◽  
Francesco Nicolini ◽  
Joseph I. Hoare ◽  
Stephen Metcalf ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Damage Tolerance ◽  
Tumour Response ◽  
In Vivo Model ◽  
High Grade ◽  
Dna Damage Tolerance ◽  
Platinum Sensitivity ◽  
Platinum Resistant ◽  
Mechanistic Investigation

AbstractHigh-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine’s predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.

scholarly journals Nelfinavir induces cytotoxicity towards high-grade serous ovarian cancer cells regardless of platinum sensitivity, involving induction of the unfolded protein response, modulation of protein synthesis, DNA damage, lysosomal impairment, and potentiation of toxicity caused by proteasome inhibition

2021 ◽  
Author(s):  
Mahbuba R Subeha ◽  
Alicia A Goyeneche ◽  
Prisca Bustamante ◽  
Michael A Lisio ◽  
Julia V Burnier ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Protein Synthesis ◽  
Rapid Development ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Platinum Sensitivity ◽  
Dose Dependent

High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Traditional treatment consists of platinum-based therapy; however, rapid development of platinum resistance contributes to lower life expectancy, warranting newer therapies to supplement the current platinum-based protocol. Repurposing market-available drugs as cancer therapeutics is a cost- and time-effective way to avail new therapies to drug-resistant patients. The anti-HIV agent nelfinavir (NFV) has shown promising toxicity against various cancers; however, its role against HGSOC is unknown. Here, we studied the effect of NFV against HGSOC cells obtained from patients along disease progression and carrying different sensitivities to platinum. NFV triggered, independently of platinum sensitivity, a dose-dependent reduction of HGSOC cell number and viability, and a parallel increase in hypo-diploid DNA content. Moreover, a dose-dependent reduction of clonogenic survival of cells escaping the acute toxicity was indicative of long-term residual damage. In addition, dose- and time-dependent phosphorylation of gama-H2AX indicated NFV-mediated DNA damage, which was associated with decreased proliferation signals driven by the AKT and ERK pathways. NFV also mediated a dose-dependent increase in endoplasmic reticulum stress-related molecules associated with long-term inhibition of protein synthesis and concurrent cell death; such events were accompanied by a proapoptotic environment, signaled by increased phospho-eIF2-alpha, ATF4, and CHOP, increased Bax/Bcl-2 ratio, and cleaved executer caspase-7. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.

scholarly journals High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenwen Guo ◽  
Xue He ◽  
Jing Ni ◽  
Liya Ma ◽  
Xianzhong Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Gene Set ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Sensitive Group

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q < 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p < 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

scholarly journals Novel conserved motifs in Rev1 C-terminus are required for mutagenic DNA damage tolerance

DNA Repair ◽  
2008 ◽  
Vol 7 (9) ◽  
pp. 1455-1470 ◽  
Author(s):  
Sanjay D'Souza ◽  
Lauren S. Waters ◽  
Graham C. Walker
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Dna Damage Tolerance ◽  
Conserved Motifs ◽  
C Terminus

scholarly journals DNA-damage tolerance mediated by PCNA•Ub fusions in human cells is dependent on Rev1 but not Polη

2013 ◽  
Vol 41 (15) ◽  
pp. 7356-7369 ◽  
Author(s):  
Zhoushuai Qin ◽  
Mengxue Lu ◽  
Xin Xu ◽  
Michelle Hanna ◽  
Naoko Shiomi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Damage Tolerance ◽  
Human Cells ◽  
Dna Damage Tolerance

scholarly journals Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer

2020 ◽  
Author(s):  
Yan Rong ◽  
Li Li
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Data ◽  
First Line ◽  
Clinical Value ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Line Chemotherapy ◽  
Sensitive Group

Abstract Objectives: To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.Method: HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.Results: 16 patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p<0.0001, p<0.0001) as well as CA125 after 1st cycle chemotherapy (p<0.0001, p<0.0001).Conclusions: Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.

Mutational profiles of ovarian cancer in Chinese patients revealed potential therapeutic targets and prognostic markers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17525-e17525
Author(s):  
Weiwei Feng ◽  
Tianjiao Lyu ◽  
Hua Liu ◽  
Yahui Jiang ◽  
Lifei Shen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Prognostic Markers ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Chinese Patients ◽  
Disease Stage ◽  
Platinum Sensitivity ◽  
Platinum Resistant

e17525 Background: Ovarian cancer (OC) is a common and lethal gynecologic malignancy. The prognosis of OC is variable among different patients treated with standard of care therapies. Herein, we described mutational profiles of OC to identify underlying therapeutic targets and prognostic markers. Methods: The study was performed in 38 Chinese patients with high-grade serous ovarian cancer (HGSC), the most common subtype of OC. Most patients (86.8%) had advanced disease (stage III-IV). Tissue samples were subjected to capture-based targeted sequencing using a panel consisting of 520 cancer related genes. Mutational profiles including gene mutations and copy number variations (CNVs) were evaluated in each patient. Homologous recombination deficiency (HRD) status was also assessed. Analysis of mutational profile with platinum-sensitivity, progression-free survival (PFS) and platinum-free interval (PFI) were performed. Results: Genetic alterations were mainly identified in TP53 (97%), BRCA1 (24%), RB1 (21%), FGF23 (21%), CCND2 (18%), RECQL4 (18%) and NF1 (16%). CNVs were comprehensively distributed in 242 genes with 76% (29/38) of patients harboring at least one CNV. In addition to BRCA1, genetic alterations were also presented in other homologous recombination repair (HRR) genes including CDK12 (5%), BRCA2 (3%), ATM (3%), BRIP1 (3%), CHEK1 (3%) and FANCI (3%). There were 22 of 38 (58%) patients with genetic alterations of the HRR pathway. In the study, 28 patients were platinum-sensitive (74%) and 10 were platinum-resistant (26%). Platinum-sensitivity was significantly associated with BRCA1/2 mutations (p < 0.01). In platinum-resistant patients, 7 of 10 patients harbored genetic alterations of actionable therapeutic targets such as PIK3CA, TSC1 and HER2 alterations. The prognosis analysis indicated that BRCA1/2 mutations were significantly associated with improved PFI (p < 0.05) and marginally associated with improved PFS (p = 0.05). Although no association was observed between HRD status and patient prognosis, subgroup analysis in patients with R0 resection found positive HRD showing significant association with better PFI (p < 0.05) and marginal association with better PFS (p = 0.06). Further analysis of HRD classified by NF1 revealed different PFS and PFI among patients harboring positive HRD, negative HRD with NF1 mutations and negative HRD with wild type NF1 (p < 0.05). The study also observed association of LRP1B mutations and RAD52 amplification with worse PFS (p < 0.05). Conclusions: In OC patients, genetic mutations were frequently occurred in both HRR and non HRR genes. CNVs were widely presented in many genes and patients. The mutational profiling also identified a number of potential therapeutic targets and prognostic markers at molecular level which could contribute to personalized treatment and management of OC.

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