Frequently deleted genes in ovarian cancer as indicators of platinum response.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5583-5583
Author(s):  
Scooter Willis ◽  
Victor Manuel Villalobos ◽  
Brandon Michael Young ◽  
Branimir I. Sikic ◽  
Brian Leyland-Jones
Keyword(s):  
Ovarian Cancer ◽  
Gene Signature ◽  
Replication Study ◽  
Rank Test ◽  
Outcome Analysis ◽  
Platinum Resistance ◽  
P Value ◽  
Full Cohort ◽  
Gene Signatures ◽  
Platinum Sensitivity

5583 Background: Integrating chromosomal deletions/amplifications with sequencing alterations is increasingly important in the determination of key drivers of outcome in cancer (Leary 2008, Curtis 2012). We introduce a novel computational approach, Gene Set Outcome Analysis, to determine gene signatures constrained to regions with frequent deletion or amplification events in ovarian cancer identified by TCGA. Differential expressions of mRNA from these genes are used as a proxy for loss of function from deletions or amplifications. Methods: Gene signatures from each region were evaluated using log-rank test comparing high and low gene expression groups split by cohort mean. In total, 30,119,708 signatures constrained to 47 deleted and 36 amplified regions were tested for PFS for first line platinum treatment in a random 2/3 split of TCGA ovarian cohort (n=262) resulting in 26,271 gene signatures with p < .001. The remaining 1/3 cohort (n=135) and full cohort (n=397) were used as a replication study where 111 signatures have a p < .01 located in 2 deletion and 1 amplification region. The signature with the lowest p-value from each region that validated in the replication study, were evaluated in GSE9891 (n=179) (Tothill 2008) for PFS when treated with platinum and taxol resulting in gene signatures from 2 deletion regions with p<.05. Results: Greater than mean expression in this gene signature [OXTR, SATB1, WNT7A, SH3BP5, CRBN, ATG7, CRELD1, TMEM43] located at 3p23-p26.2 predicts poor response to platinum chemotherapy in TCGA full ovarian cohort (17.9 vs 14 months p = 1.4E-7) and validates in GSE9891 (19.6 vs 13.3 months p = .014). Using a separate, compact gene signature [CAAP1, LRRC19, IFNA8] located at 9p21.2, samples with lower than mean expression demonstrate increased platinum sensitivity in TCGA full ovarian cohort (12.2 vs 18.2 months p = 1.0E-6) and in GSE9891 (15.5 vs 18.6 p = .055). Conclusions: Response to platinum therapy is an important predictor of survival in high-risk ovarian cancer patients. These signatures arising from common deletion and amplification events in ovarian cancer can anticipate platinum sensitivity and merits further study for use in choosing optimal therapies studying platinum resistance mechanisms.

scholarly journals A Network Analysis of Multiple Myeloma Related Gene Signatures

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1452 ◽  
Author(s):  
Yu Liu ◽  
Haocheng Yu ◽  
Seungyeul Yoo ◽  
Eunjee Lee ◽  
Alessandro Laganà ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Response ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Risk Groups ◽  
Rank Test ◽  
P Value ◽  
Causal Network ◽  
Gene Signatures ◽  
Network Analyses

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this study, we analyzed gene expression, copy number variation, and clinical data from the Multiple Myeloma Research Consortium (MMRC) dataset and constructed a multiple myeloma molecular causal network (M3CN). The M3CN was used to unify eight prognostic gene signatures in the literature that shared very few genes between them, resulting in a prognostic subnetwork of the M3CN, consisting of 178 genes that were enriched for genes involved in cell cycle (fold enrichment = 8.4, p value = 6.1 × 10−26). The M3CN was further used to characterize immunomodulators and proteasome inhibitors for MM, demonstrating the pleiotropic effects of these drugs, with drug-response signature genes enriched across multiple M3CN subnetworks. Network analyses indicated potential links between these drug-response subnetworks and the prognostic subnetwork. To elucidate the structure of these important MM subnetworks, we identified putative key regulators predicted to modulate the state of these subnetworks. Finally, to assess the predictive power of our network-based models, we stratified MM patients in an independent cohort, the MMRF-CoMMpass study, based on the prognostic subnetwork, and compared the performance of this subnetwork against other signatures in the literature. We show that the M3CN-derived prognostic subnetwork achieved the best separation between different risk groups in terms of log-rank test p-values and hazard ratios. In summary, this work demonstrates the power of a probabilistic causal network approach to understanding molecular mechanisms underlying the different MM signatures.

A 13-Glycosylation Gene Signature in Multiple Myeloma Can Predicts Survival and Identifies Candidates for Targeted Therapy (GiMM13)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4423-4423 ◽  
Author(s):  
Caoilfhionn Connolly ◽  
Alokkumar Jha ◽  
Alessandro Natoni ◽  
Michael E O'Dwyer
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
Rank Test ◽  
P Value ◽  
Log Rank Test ◽  
Novel Approach

Abstract Introduction Advances in genomics have highlighted the potential for individualized prognostication and therapy in multiple myeloma (MM). Previously developed gene expression signatures have identified patients with high risk (Kuiper et al, Blood 2016) however, they provide few insights into underlying disease biology thereby limiting their use in informing treatment decisions. Glycosylation is deregulated in MM (Glavey et al), and potential consequences include altered cell adhesion, signaling, immune evasion and drug resistance. In this study we have utilized RNA sequencing data from the IA7 CoMMpass cohort to characterize the expression profile of genes involved in glycosylation. This represents a novel approach to identify a distinct molecular pathway related to outcome, which is potentially actionable. Methods A pathway based approach was adopted to evaluate genes implicated in glycosylation, including the generation of selectin ligands. A literature review and KEGG pathway analysis of pathways relating to O-glycans, N-glycans, sialic acid metabolism, glycolipid synthesis and metabolism was completed. RNA Cufflinks-gene level FPKM expression of 458 patients enrolled in the IA7 cohort of the Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) were analysed as derivation cohort. We developed expression cut-offs using a novel approach of adjusted existing linear regression model to define the gene expression cut-off by applying 3rd Quartile data (q1+q2/2-qmin). The analysis of overall survival (OS) was completed using adjusted 'kpas' R-package according to our cut-off model. Association between individual transcripts and OS was analyzed with log-rank test. Genes with p-value <0.2 were used in subsequent prioritization analysis. This cut-off methodology was employed to define the nearest neighbor for a gene for Gene Set Enrichment Analysis (GSEA). As far as 4th neighbor above and below the cut off was used to have centrally driven gene selection method for prioritization. The gene signature was validated in GSE2658 (Shaughnessy et al) dataset. Results Initial analysis yielded 184 prospective genes. 147 were significant on univariate analysis. Following further prioritization of these genes, we identified thirteen genes that had significant impact upon outcomes (GiMM13). Figure 1 reveals that GiMM13 signature has a significant correlation with inferior OS (HR 4.66 p-value 0.022). The prognostic impact of stratifying GiMM13 positive (High risk) or GiMM13 negative (Low risk) by ISS stage was evaluated. In Table 1. Kaplan Meier estimates generated for GiMM13 (High) or GiMM13 (Low) stratified by ISS are compared statistically using the log rank test. The prognostic ability of GiMM13 to synthesize distinct subgroups relative to each ISS stage is shown in Figure 2. ISS1-Low is the the lowest risk group with best prognosis. Hazard ratios relative to the ISS1-Low group were 1.8, p-value 0.029 (ISS2-Low), 2.1, p-value 0.031 (ISS3-Low), 4.3, p-value 0.04 (ISS1-HR), 5.9, p-value 0.039 (ISS2-HR) and 3.1, p-value 0.001 (ISS3-HR). The GiMM13 signature enhances the prognostic ability of ISS to identify patients with inferior or superior outcomes respectively. Conclusion While the therapeutic armamentarium for MM has expanded considerably, the significant molecular heterogeneity in the disease still poses a significant challenge. Our data suggests aberrant transcription of glycosylation genes, involved predominantly in selectin ligand synthesis, is associated with inferior survival outcomes and may help identify patients likely to benefit from treatment with agents targeting aberrant glycosylation, e.g. E-selectin inhibitor. Consistent with recent findings in chemoresistant minimal residual disease (MRD) (Paiva et al, Blood 2016), it would appear that O-glycosylation, rather than N-glycosylation is most significantly implicated in this biological processes conferring inferior outcomes. In conclusion, using a novel pathway-based approach to identify a 13-gene signature (GiMM13), we have developed a robust tool that can refine patient prognosis and inform clinical decision-making. Acknowledgment These data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives (https://research.themmrf.org and www.themmrf.org). Disclosures O'Dwyer: Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Epidermal growth factor receptor (EGFR) mutation rate in advanced ovarian cancer (AOC): Results of a prospective study in Caucasian patients (pts)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13127-13127
Author(s):  
A. Mustea ◽  
D. Koensgen ◽  
R. Zeillinger ◽  
D. C. Castillo-Tong ◽  
P. Sun ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Descriptive Analysis ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Kinase Domain ◽  
Rank Test ◽  
P Value ◽  
Egfr Gene

13127 Background: The EGFR is over expressed in 55% to 98% of advanced epithelial ovarian carcinoma. Different studies demonstrated EGFR status as an independent prognostic factor for OC. Recent studies in non small cell lung cancer suggest that the presence of the clinical response to tyrosine kinase inhibitors (e.g. ZD 1839) correlates with the somatic mutations in the kinase domain of EGFR, exons 18–21. For pts with OC data are not available on EGFR gene mutation. Methods: Shock-frozen samples from 32 patients (pts) with primary of ovarian cancer were stratified in two groups according to disease-free interval: ≤6 months (17 pts.) and <6 months (15 pts.). All pts were prospectively collected within Tumor bank Ovarian Cancer Project. Patient collective consisted only from west European Caucasian women. Additionally, 9 commercial available ovarian cancer cell lines (TOV-90, TOV-112D, TOV-21G, OVCAR-3, A2780, A2780 ADR, ES-2, SK-OV-3, and Caov-3) and 32 established ovarian cancer lines were analysed. Exon sequencing of genomic DNA was used to detect L858R deletion mutations of EGFR within exons 21 of the kinase domain. PCR and capillary electrophoresis (Chip-Format) were used to analyse 15 bp deletion in Exon 19. We focused on descriptive analysis. The Log-Rank test was applied to confirm statistically significance (p-value of <0.05). Results: Overall, 74.6% of the pts. were diagnosed FIGO stage III-IV. Median follow-up period was: 14.17 month (range: 2–42 months). Whether in cell lines, nor in tumor samples, stratified to response of platinum therapy any mutation of EGFR gene was observed. Conclusions: Our study indicates that the prevalence of mutation in the kinase domain of EGFR, exons 19 and 21 seems to be very low in pts. with AOC. Further studies should investigate other ethical groups of pts. No significant financial relationships to disclose.

scholarly journals Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer

2021 ◽  
Author(s):  
Ryusuke Murakami ◽  
Junzo Hamanishi ◽  
J. B. Brown ◽  
Kaoru Abiko ◽  
Koji Yamanoi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Response ◽  
Clear Cell ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Specific Gene ◽  
Gene Signatures ◽  
Gene Set ◽  
Platinum Resistant

Abstract Background Based on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n=19, UMIN000005714), we aimed to identify the therapeutic response biomarkers to nivolumab in ovarian cancer. Methods Tumor gene expressions were evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas in The Cancer Genome Atlas and a signature established prior to ovarian clear cell carcinoma. Gene sets were scored using the single-sample gene set enrichment analysis, and resulting scores were used to assess the correlation between each gene set and the clinical response to nivolumab therapy. Statistical analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) groups. Results The clear cell gene signature significantly had higher score in the CR group, and the proliferative gene signature had significantly higher score in the PD group where nivolumab was not effective (respective p-values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. Conclusion Ovarian cancer-specific gene signature and related pathway scores provide a preliminary indicator for ovarian cancer prior to receiving anti-PD-1 antibody therapy.

Prediction of survival in patients with epithelial ovarian cancer based on the timing and rate of normalization of CA125 levels during primary chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5585-5585
Author(s):  
K. S. Matthews ◽  
R. P. Rocconi ◽  
M. Kemper ◽  
K. E. Hoskins ◽  
W. K. Huh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Eligible Patient ◽  
Primary Chemotherapy ◽  
Rank Test ◽  
Primary Therapy ◽  
Linear Regression Models ◽  
Platinum Sensitivity ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy

5585 Objective: CA125 is the tumor marker used to evaluate response to chemotherapy in patients with epithelial ovarian cancer (EOC). The aim of this study was to determine if the timing of normalization or percent decrease in CA125 levels during primary chemotherapy could predict survival. Methods: Patients treated at our institution for EOC with primary taxane/platinum-based chemotherapy for 6 cycles between 1996 and 2005 were eligible. Patient demographics, chemotherapy administration, CA125 levels, and survival outcomes were abstracted. Progression-free- survival (PFS), overall survival (OS), and platinum sensitivity (> 6 months from chemotherapy completion) were compared to CA125 levels during primary therapy. Baseline levels, change over time, and timing of CA125 normalization were calculated. Analyses were performed using Kaplan-Meier method and compared using the log-rank test, Chi-square test and Fischer’s exact test. Results: 269 patients with EOC were identified. When stratified by which cycle of chemotherapy achieved normalization, PFS ranged from 25 months at 1st cycle to 4 months at 6th cycle (p< 0.001). OS showed a similar benefit from 74 months at 1st cycle to 22 months at 6th cycle (p<0.001). Platinum sensitivity improved from 23% (normal CA125 after 6th cycle) to 72% (normal CA125 after 1st cycle) (p=0.003). Patients with normalization after the 3rd cycle or sooner compared to patients with normalization after the 4th cycle demonstrated improved PFS (19 vs. 6 months; p<0.001), OS (48 vs. 27 months; p=0.001) and platinum sensitivity (78 vs. 22%; p<0.001). Linear regression models of the slope of the decline of CA125 levels correlated with PFS (p=0.03); however, the models failed to predict an OS advantage. Conclusion: Earlier normalization of CA125 levels during primary chemotherapy for EOC predicts improvement in platinum sensitivity, PFS, and OS. This data provides prognostic information that may influence future decisions regarding chemotherapy. No significant financial relationships to disclose.

scholarly journals RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 476
Author(s):  
Karolin Heinze ◽  
Martin Hölzer ◽  
Martin Ungelenk ◽  
Melanie Gerth ◽  
Jürgen Thomale ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Transcript Variant ◽  
Platinum Resistance ◽  
Chemotherapy Response ◽  
Proteomic Profiling ◽  
Platinum Sensitivity ◽  
Γh2ax Foci ◽  
Angiogenesis Assay ◽  
Transcript Variants ◽  
Skov3 Cells

The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3—regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes—platinum resistance and angiogenesis.

scholarly journals Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryusuke Murakami ◽  
Junzo Hamanishi ◽  
J. B. Brown ◽  
Kaoru Abiko ◽  
Koji Yamanoi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Response ◽  
Clear Cell ◽  
Response Prediction ◽  
Complete Response ◽  
Gene Signature ◽  
Specific Gene ◽  
Gene Signatures ◽  
Platinum Resistant ◽  
Visual Projection

AbstractBased on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n = 19, UMIN000005714), we aimed to identify the biomarkers predictive of response. Tumor gene expression was evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas and a signature established prior for ovarian clear cell carcinoma. Resulting signature scores were statistically assessed with both univariate and multivariate approaches for correlation to clinical response. Analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) patient groups. The clear cell gene signature was scored significantly higher in the CR group, and the proliferative gene signature had significantly higher scores in the PD group where nivolumab was not effective (respective p values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. An applicable clinical response prediction formula was derived. Ovarian cancer-specific gene signatures and related pathway scores provide a robust preliminary indicator for ovarian cancer patients prior to anti-PD-1 therapy decisions.

scholarly journals A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5215
Author(s):  
Caitlin Phillips-Chavez ◽  
Jermaine Coward ◽  
Michael Watson ◽  
Janet Schloss
Keyword(s):  
Ovarian Cancer ◽  
Survival Rate ◽  
Serum Folate ◽  
Platinum Resistance ◽  
Aberrant Methylation ◽  
Dietary Zinc ◽  
Mthfr Polymorphism ◽  
Mthfr Polymorphisms ◽  
Platinum Sensitivity

Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC.

scholarly journals CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0251079
Author(s):  
Yoshiko Oyama ◽  
Shogo Shigeta ◽  
Hideki Tokunaga ◽  
Keita Tsuji ◽  
Masumi Ishibashi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
The Cancer Genome Atlas ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Nucleosome Remodeling ◽  
Platinum Sensitivity ◽  
Mdr1 Expression ◽  
Platinum Agents

Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.

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