@article{83c03549dec542bda46623e9370b5010,
title = "Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer",
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",
author = "Dongqing Huang and Shrabanti Chowdhury and Hong Wang and Savage, {Sara R.} and Ivey, {Richard G.} and Kennedy, {Jacob J.} and Whiteaker, {Jeffrey R.} and Chenwei Lin and Xiaonan Hou and Oberg, {Ann L.} and Larson, {Melissa C.} and Najmeh Eskandari and Delisi, {Davide A.} and Saverio Gentile and Huntoon, {Catherine J.} and Voytovich, {Uliana J.} and Shire, {Zahra J.} and Qing Yu and Gygi, {Steven P.} and Hoofnagle, {Andrew N.} and Herbert, {Zachary T.} and Lorentzen, {Travis D.} and Anna Calinawan and Karnitz, {Larry M.} and Weroha, {S. John} and Kaufmann, {Scott H.} and Bing Zhang and Pei Wang and Birrer, {Michael J.} and Paulovich, {Amanda G.}",
note = "Funding Information: We thank Anna Lokshin and Katherine Aird (University of Pittsburgh) and Toshiyasu Taniguchi (Fred Hutchinson Cancer Research Center) for the FT-4 and the PEO1S and PEO4R cell lines, respectively. We thank Taro Hitosugi (Mayo Clinic) for retroviral human CPT1A constructs. This work was done with funding from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium and supported by National Institutes of Health grants U01CA214114 (A.G.P. and M.J.B.), R50CA211499 (J.R.W.), U24CA210993 (P.W.), U24CA210954 (B.Z.), P50CA136393 (S.H.K), and S10OD028685 (A.G.P); U.S. Department of Defense (DOD) grants W81XWH-20-1-046 (S.G.) and W81XWH-16-2-0038 (M.J.B.); and generous support from the Aven Foundation (A.G.P.) and the Christl Burgess Memorial Fund for ovarian cancer research (S.G.). Conceptualization, A.N.H. L.M.K. S.J.W. S.H.K. P.W. S.G. M.J.B. and A.G.P.; methodology, S.P.G. L.M.K. S.J.W. S.H.K. B.Z. P.W. S.G. M.J.B. and A.G.P.; software, S.C. S.R.S. C.L. A.C. and P.W.; validation, H.W. R.G.I. J.J.K. Q.Y. and S.P.G.; formal analysis, S.C. S.R.S. C.L. A.C. and P.W.; investigation, H.W. R.G.I. J.J.K. X.H. N.E. D.A.D. C.J.H. U.J.V. Z.J.S. Q.Y. S.P.G. and Z.T.H.; resources, H.W. R.G.I. J.J.K. X.H. Z.J.S. T.D.L. Q.Y. S.P.G. Z.T.H. L.M.K. S.J.W. S.H.K. and M.J.B.; data curation, S.C. S.R.S. R.G.I. J.J.K. C.L. A.C. and P.W.; writing ? original draft, D.H. S.C. H.W. S.R.S. R.G.I. J.J.K. Q.Y. L.M.K. S.J.W. S.H.K. P.W. M.J.B. and A.G.P.; writing ? review & editing, D.H. S.C. H.W. S.R.S. R.G.I. J.J.K. J.R.W. A.N.H. T.D.L. L.M.K. S.J.W. S.H.K. S.G. P.W. M.J.B. and A.G.P.; visualization, D.H. S.C. H.W. S.R.S. S.G. P.W. M.J.B. and A.G.P.; supervision, P.W. M.J.B. and A.G.P.; project administration, J.R.W. T.D.L. L.M.K. S.J.W. S.H.K. B.Z. P.W. M.J.B. and A.G.P.; funding acquisition, M.J.B. and A.G.P. M.J.B. has participated in advisory boards for Clovis, Astra Zeneca, and GSK-Tesaro. A.N.H. has a financial interest in the company Seattle Genetics. Funding Information: We thank Anna Lokshin and Katherine Aird (University of Pittsburgh) and Toshiyasu Taniguchi (Fred Hutchinson Cancer Research Center) for the FT-4 and the PEO1 S and PEO4 R cell lines, respectively. We thank Taro Hitosugi (Mayo Clinic) for retroviral human CPT1A constructs. This work was done with funding from the National Cancer Institute{\textquoteright}s Clinical Proteomic Tumor Analysis Consortium and supported by National Institutes of Health grants U01CA214114 (A.G.P. and M.J.B.), R50CA211499 (J.R.W.), U24CA210993 (P.W.), U24CA210954 (B.Z.), P50CA136393 (S.H.K), and S10OD028685 (A.G.P); U.S. Department of Defense (DOD) grants W81XWH-20-1-046 (S.G.) and W81XWH-16-2-0038 (M.J.B.); and generous support from the Aven Foundation (A.G.P.) and the Christl Burgess Memorial Fund for ovarian cancer research (S.G.). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = dec,
day = "21",
doi = "10.1016/j.xcrm.2021.100471",
language = "English (US)",
volume = "2",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "12",
}