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Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer

ABSTRACT: Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163152 | GEO | 2022/01/04

REPOSITORIES: GEO

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Multiomic analysis implicates OXPHOS/fatty acid oxidation as a potential druggable target in platinum-resistant high grade serous ovarian cancer

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2021-12-22 | PXD020764 | Pride

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [ID8 and ID8-IP / KMF cells]

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2019-07-01 | GSE129097 | GEO

FDXR Drives Primary and Endocrine Resistant Tumor Cell Growth in ER+ Breast Cancer via CPT1A-Mediated Fatty Acid Oxidation

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2023-05-24 | GSE217902 | GEO

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [KMF parental, KMF clone KT13 (FAK-/-), KT13 + GFP-FAK, KT13 + GFP-FAK R454, and KT13 + deltaGSK beta-catenin]

2019-07-01 | GSE129098 | GEO

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2022-02-02 | GSE168225 | GEO

Sequential azacitidine and carboplatin can prime high-grade serous ovarian cancer to respond to checkpoint inhibitor immunotherapy.

2022-02-02 | GSE169617 | GEO

Platinum chemotherapy induces diverse evolutionary trajectories in high grade serous ovarian cancer

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2022-08-01 | GSE141630 | GEO

Proteomic analysis of tumor tissues form high-grade serous ovarian cancer patients

Project description:In the present project, in order to explore the molecular basis of platinum resistance and further determine potential biomarkers and therapeutic targets for high-grade serous ovarian cancer (HGSOC), we conducted a comparative proteomic analysis to identify the differentially expressed proteins between tumor tissues from platinum-sensitive and platinum-resistant HGSOC patient groups.

2021-09-30 | PXD028225 | iProX

Epigenetic regulation of the homeobox gene MSX1 associates with platinum resistant disease in high grade serous epithelial ovarian cancer

Project description:Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance. Bisulphite converted DNA from the 86 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2

2015-11-26 | E-GEOD-75414 | biostudies-arrayexpress

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2015-01-28 | PXD001186 | Pride

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