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

Cell Rep Med. 2021 Dec 21;2(12):100471. doi: 10.1016/j.xcrm.2021.100471.

Abstract

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).

Keywords: CPT1A; carboplatin; fatty acid oxidation; ovarian cancer; oxidative phosphorylation; proteogenomic; proteomic; reactive oxygen species; resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Apoptosis / drug effects
  • Carboplatin / pharmacology
  • Carboplatin / therapeutic use*
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / metabolism*
  • Cystadenocarcinoma, Serous / pathology*
  • DNA Damage
  • Drug Resistance, Neoplasm / drug effects
  • Fatty Acids / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genomics*
  • Humans
  • Mice, SCID
  • Molecular Targeted Therapy*
  • Neoplasm Grading
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology*
  • Oxidation-Reduction / drug effects
  • Oxidative Phosphorylation / drug effects
  • Phosphoproteins / metabolism
  • Proteomics
  • Reactive Oxygen Species / metabolism

Substances

  • Fatty Acids
  • Phosphoproteins
  • Reactive Oxygen Species
  • Carboplatin
  • CPT1A protein, human
  • Carnitine O-Palmitoyltransferase
  • ACACB protein, human
  • Acetyl-CoA Carboxylase