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

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