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Design of combination therapeutics from protein response to drugs in ovarian cancer cells

ABSTRACT: High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy and novel treatment approaches are needed. Here, we used unbiased quantitative protein mass spectrometry to assess the cellular response profile to drug perturbations in ovarian cancer cells for the rational design of potential combination therapies. Analysis of the perturbation profiles revealed proteins responding across several drug perturbations (called frequently responsive below) as well as drug-specific protein responses. The frequently responsive proteins included proteins that reflected general drug resistance mechanisms such as changes in drug efflux pumps. Network analysis of drug-specific protein responses revealed known and potential novel markers of resistance, which were used to rationalize the design of anti-resistance drug pairs. We experimentally tested the anti-proliferative effects of 12 of the proposed drug combinations in 6 HGSOC cell lines. Drug combinations tested with additive or synergistic effects are plausible candidates for overcoming or preventing resistance to single agents; these include several combinations that were synergistic (with PARPi, MEKi, and SRCi). Additionally, we observed 0.05-0.11 micromolar response to GPX4 inhibitors as single agents in the OVCAR-4 cell line. We propose several drug combinations as potential therapeutic candidates in ovarian cancer, as well as GPX4 inhibitors as single agents

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Cell Culture

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Fabian Coscia

LAB HEAD: Fabian Coscia

PROVIDER: PXD066316 | Pride | 2025-07-19

REPOSITORIES: Pride

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			Action	DRS
	20190827_001454_201_Report_proteingroups.txt	Txt
	Rawfiles_part1.zip	Other
	Rawfiles_part2.zip	Other
	Sample_annotation.xlsx	Xlsx

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Project description:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments

Project description:Background In the ongoing battle against BCR-ABL+ leukemia, despite significant advances with tyrosine kinase inhibitors (TKIs), the persistent challenges of drug resistance and the enduring presence of leukemic stem cells (LSCs) remain formidable barriers to achieving a cure. Methods In this study, we demonstrated that Disulfiram (DSF) induces ferroptosis to synergize with TKIs in inhibiting BCR-ABL+ cells, particularly targeting resistant cells and LSCs, using cell models, mouse models, and primary cells from patients. We elucidated the mechanism by which DSF promotes GPX4 degradation to induce ferroptosis through immunofluorescence, co-immunoprecipitation (CO-IP), RNA sequencing, lipid peroxidation assays, and rescue experiments. Results Here, we present compelling evidence elucidating the sensitivity of DSF, an FDA-approved drug for alcohol dependence, towards BCR-ABL+ cells. Our findings underscore DSF's ability to selectively induce a potent cytotoxic effect on BCR-ABL+ cell lines and effectively inhibit primary BCR-ABL+ leukemia cells. Crucially, the combined treatment of DSF with TKIs selectively eradicates TKI-insensitive stem cells and resistant cells. Of particular note is DSF's capacity to disrupt GPX4 stability, elevate the labile iron pool, and intensify lipid peroxidation, ultimately leading to ferroptotic cell death. Our investigation shows that BCR-ABL expression induces alterations in cellular iron metabolism and increases GPX4 expression. Additionally, we demonstrate the indispensability of GPX4 for LSC development and the initiation/maintenance of BCR-ABL+ leukemia. Mechanical analysis further elucidates DSF's ability to circumvent resistance by reducing GPX4 levels through the disruption of its binding with HSPA8, thereby promoting GPX4 ubiquitination and subsequent degradation. Furthermore, the combined treatment of DSF with TKIs effectively targets both BCR-ABL+ blast cells and drug-insensitive LSCs, conferring a significant survival advantage in mouse models. Conclusion In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.

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Design of combination therapeutics from protein response to drugs in ovarian cancer cells

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