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. Hoofnagle; Zachary 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

doi:10.1016/j.xcrm.2021.100471

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 journal › Article › peer-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 language	English (US)
Article number	100471
Journal	Cell Reports Medicine
Volume	2
Issue number	12
DOIs	https://doi.org/10.1016/j.xcrm.2021.100471
State	Published - Dec 21 2021

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2021.100471

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Huang, D., Chowdhury, S., Wang, H., Savage, S. R., Ivey, R. G., Kennedy, J. J., Whiteaker, J. R., Lin, C., Hou, X., Oberg, A. L., Larson, M. C., Eskandari, N., Delisi, D. A., Gentile, S., Huntoon, C. J., Voytovich, U. J., Shire, Z. J., Yu, Q., Gygi, S. P., ... Paulovich, A. G. (2021). Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer. Cell Reports Medicine, 2(12), Article 100471. https://doi.org/10.1016/j.xcrm.2021.100471

Huang, D, Chowdhury, S, Wang, H, Savage, SR, Ivey, RG, Kennedy, JJ, Whiteaker, JR, Lin, C, Hou, X, Oberg, AL, Larson, MC, Eskandari, N, Delisi, DA, Gentile, S, Huntoon, CJ, Voytovich, UJ, Shire, ZJ, Yu, Q, Gygi, SP, Hoofnagle, AN, Herbert, ZT, Lorentzen, TD, Calinawan, A, Karnitz, LM , Weroha, SJ , Kaufmann, SH, Zhang, B, Wang, P, Birrer, MJ & Paulovich, AG 2021, 'Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer', Cell Reports Medicine, vol. 2, no. 12, 100471. https://doi.org/10.1016/j.xcrm.2021.100471

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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 = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = dec,

day = "21",

doi = "10.1016/j.xcrm.2021.100471",

language = "English (US)",

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T1 - Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

AU - Huang, Dongqing

AU - Chowdhury, Shrabanti

AU - Wang, Hong

AU - Savage, Sara R.

AU - Ivey, Richard G.

AU - Kennedy, Jacob J.

AU - Whiteaker, Jeffrey R.

AU - Lin, Chenwei

AU - Hou, Xiaonan

AU - Oberg, Ann L.

AU - Larson, Melissa C.

AU - Eskandari, Najmeh

AU - Delisi, Davide A.

AU - Gentile, Saverio

AU - Huntoon, Catherine J.

AU - Voytovich, Uliana J.

AU - Shire, Zahra J.

AU - Yu, Qing

AU - Gygi, Steven P.

AU - Hoofnagle, Andrew N.

AU - Herbert, Zachary T.

AU - Lorentzen, Travis D.

AU - Calinawan, Anna

AU - Karnitz, Larry M.

AU - Weroha, S. John

AU - Kaufmann, Scott H.

AU - Zhang, Bing

AU - Wang, Pei

AU - Birrer, Michael J.

AU - Paulovich, Amanda G.

PY - 2021/12/21

Y1 - 2021/12/21

N2 - 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).

AB - 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).

KW - CPT1A

KW - carboplatin

KW - fatty acid oxidation

KW - ovarian cancer

KW - oxidative phosphorylation

KW - proteogenomic

KW - proteomic

KW - reactive oxygen species

KW - resistance

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DO - 10.1016/j.xcrm.2021.100471

M3 - Article

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AN - SCOPUS:85121490443

SN - 2666-3791

VL - 2

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 12

M1 - 100471

ER -

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

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