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

Dongqing Huang, Shrabanti Chowdhury, Hong Wang, Sara R. Savage, Richard G. Ivey, Jacob J. Kennedy, Jeffrey R. Whiteaker, Chenwei Lin, Xiaonan Hou, Ann L. Oberg, Melissa C. Larson, Najmeh Eskandari, Davide A. Delisi, Saverio Gentile, Catherine J. Huntoon, Uliana J. Voytovich, Zahra J. Shire, Qing Yu, Steven P. Gygi, Andrew N. HoofnagleZachary T. Herbert, Travis D. Lorentzen, Anna Calinawan, Larry M. Karnitz, S. John Weroha, Scott H. Kaufmann, Bing Zhang, Pei Wang, Michael J. Birrer, Amanda G. Paulovich

Research output: Contribution to journalArticlepeer-review

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).

Original languageEnglish (US)
Article number100471
JournalCell Reports Medicine
Volume2
Issue number12
DOIs
StatePublished - Dec 21 2021

Keywords

  • CPT1A
  • carboplatin
  • fatty acid oxidation
  • ovarian cancer
  • oxidative phosphorylation
  • proteogenomic
  • proteomic
  • reactive oxygen species
  • resistance

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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