PXD020764

PXD020764 is an original dataset announced via ProteomeXchange.

Title	Multiomic analysis implicates OXPHOS/fatty acid oxidation as a potential druggable target in platinum-resistant high grade serous ovarian cancer
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.
HostingRepository	PRIDE
AnnounceDate	2021-12-22
AnnouncementXML	Submission_2021-12-22_11:31:49.881.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jacob Kennedy
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	carbamoylated residue; ubiquitinylated lysine; phosphorylated residue; acetylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-06 00:22:52	ID requested
⏵ 1	2021-12-22 11:31:50	announced

Dataset with its publication pending

ProteomeXchange project tag: CPTAC Consortium

submitter keyword: Human, Ovarian cancer, Cell line, PDX, shotgun proteomics, TMT, fractionation, phosphorylation, global, acetylation, ubiquitinylation

Amanda G Paulovich
contact affiliation	Clinical Research Division, Fred Hutchinson Cancer Research Center
contact email	apaulovi@fredhutch.org
lab head
Jacob Kennedy
contact affiliation	Fred Hutchinson Cancer Research Center
contact email	jkennedy@fhcrc.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020764
     1. Label: PRIDE project
     2. Name: Multiomic analysis implicates OXPHOS/fatty acid oxidation as a potential druggable target in platinum-resistant high grade serous ovarian cancer