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

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

PROVIDER: PRJNA685120 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13251200_1.fastq.gz	Fastqsanger.gz
	SRR13251200_2.fastq.gz	Fastqsanger.gz
	SRR13251201_1.fastq.gz	Fastqsanger.gz
	SRR13251201_2.fastq.gz	Fastqsanger.gz
	SRR13251202_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2022-01-04 | GSE163152 | GEO

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

Project description:In the United States, high grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy and tumor response to platinum-based chemotherapy is a major determinant of clinical outcome. Although recent efforts have dramatically improved the median survival of advanced ovarian cancer, the initial treatment of the disease has remained the same. The initial therapy includes surgery and chemotherapy and the response rate is very high (85%). Unfortunately, 15% of patients do not respond to this therapy and have platinum-refractory disease. These patients have a very short survival and there is an urgent need to identify novel pharmaceutically targetable pathways to treat these patients. We generated extensive proteomic (global, phospho, ubiquitin, acetylation, pTyr) and RNASeq-based dynamic molecular profiles (+/-carboplatin at 8 and 24 hours) from HGSOC intra-patient cell line pairs (PEA1/PEA2, PEO1/PEO4, PEO14/PEO23) derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed a multi-faceted response to carboplatin (e.g., induction of a DNA damage response, ubiquitination of ribosomal proteins, and metabolic changes), as well as novel carboplatin-induced post-translational modifications. Higher oxidative phosphorylation (OXPHOS) and fatty acid beta-oxidation (FAO) pathway expression was observed in resistant compared with sensitive cells. These expression findings were validated via metabolite profiling of cell lines and proteomic profiling of platinum sensitive and refractory HGSOC patient derived xenograft (PDX) models. Both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents the rate limiting step of FAO, sensitizes HGSOC cells to platinum. The metabolic signature identified in the cell line and PDX models is correlated with survival in a previously reported proteomic analysis of HGSOC, and thus FAO is a candidate druggable pathway to overcome platinum resistance.

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

Project description:Resistance to platinum compounds is a major determinant of patient survival in high-grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a data resource composed of dynamic (±carboplatin) protein, post-translational modification, and RNA sequencing (RNA-seq) profiles from intra-patient cell line pairs derived from 3 HGSOC patients before and after acquiring platinum resistance. These profiles reveal extensive responses to carboplatin that differ between sensitive and resistant cells. Higher fatty acid oxidation (FAO) pathway expression is associated with platinum resistance, and both pharmacologic inhibition and CRISPR knockout of carnitine palmitoyltransferase 1A (CPT1A), which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. The results are further validated in patient-derived xenograft models, indicating that CPT1A is a candidate therapeutic target to overcome platinum resistance. All multiomic data can be queried via an intuitive gene-query user interface (https://sites.google.com/view/ptrc-cell-line).

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

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Transcriptomes of tumour-associated macrophages from high grade serous ovarian cancer pre- and post-platinum-based neoadjuvant chemotherapy.

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Proteogenomic analysis of chemo-refractory high grade serous ovarian cancer

Project description:To improve our understanding of the molecular basis of chemo-refractory high grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two independent validation cohorts (spanning four academic centers) and utilizing two biospecimen types (formalin-fixed paraffin-embedded and frozen tumor biopsies). As the largest and most comprehensive study of refractory ovarian cancers to date, this effort identified a 64-protein signature that predicts a subset of HGSOCs refractory to initial platinum-based therapy with high specificity and is validated in two independent patient cohorts. We also detected significant association between lack of Ch17 loss-of-heterozygosity and refractory disease. Moreover, based on protein pathway expression, five novel clusters of HGSOC were identified and validated across two independent patient cohorts, as well as in patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic targets.

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

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