PMID- 35028612
OWN - NLM
STAT- MEDLINE
DCOM- 20220303
LR  - 20240226
IS  - 2666-3791 (Electronic)
IS  - 2666-3791 (Linking)
VI  - 2
IP  - 12
DP  - 2021 Dec 21
TI  - Multiomic analysis identifies CPT1A as a potential therapeutic target in 
      platinum-refractory, high-grade serous ovarian cancer.
PG  - 100471
LID - 10.1016/j.xcrm.2021.100471 [doi]
LID - 100471
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).
CI  - (c) 2021 The Author(s).
FAU - Huang, Dongqing
AU  - Huang D
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Chowdhury, Shrabanti
AU  - Chowdhury S
AD  - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Wang, Hong
AU  - Wang H
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Savage, Sara R
AU  - Savage SR
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 
      77030, USA.
FAU - Ivey, Richard G
AU  - Ivey RG
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Kennedy, Jacob J
AU  - Kennedy JJ
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Whiteaker, Jeffrey R
AU  - Whiteaker JR
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Lin, Chenwei
AU  - Lin C
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Hou, Xiaonan
AU  - Hou X
AD  - Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Oberg, Ann L
AU  - Oberg AL
AD  - Department of Quantitative Health Sciences, Division of Computational Biology, 
      Mayo Clinic, Rochester, MN 55905, USA.
FAU - Larson, Melissa C
AU  - Larson MC
AD  - Department of Quantitative Health Sciences, Division of Clinical Trials and 
      Biostatistics, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Eskandari, Najmeh
AU  - Eskandari N
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Illinois, Chicago, IL 60612, USA.
FAU - Delisi, Davide A
AU  - Delisi DA
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Illinois, Chicago, IL 60612, USA.
FAU - Gentile, Saverio
AU  - Gentile S
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Illinois, Chicago, IL 60612, USA.
FAU - Huntoon, Catherine J
AU  - Huntoon CJ
AD  - Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Voytovich, Uliana J
AU  - Voytovich UJ
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Shire, Zahra J
AU  - Shire ZJ
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Yu, Qing
AU  - Yu Q
AD  - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
FAU - Gygi, Steven P
AU  - Gygi SP
AD  - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
FAU - Hoofnagle, Andrew N
AU  - Hoofnagle AN
AD  - Department of Lab Medicine, University of Washington, Seattle, WA 98195, USA.
FAU - Herbert, Zachary T
AU  - Herbert ZT
AD  - Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 
      02215, USA.
FAU - Lorentzen, Travis D
AU  - Lorentzen TD
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
FAU - Calinawan, Anna
AU  - Calinawan A
AD  - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Karnitz, Larry M
AU  - Karnitz LM
AD  - Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Weroha, S John
AU  - Weroha SJ
AD  - Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Kaufmann, Scott H
AU  - Kaufmann SH
AD  - Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Zhang, Bing
AU  - Zhang B
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 
      77030, USA.
FAU - Wang, Pei
AU  - Wang P
AD  - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount 
      Sinai, New York, NY 10029, USA.
FAU - Birrer, Michael J
AU  - Birrer MJ
AD  - University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
FAU - Paulovich, Amanda G
AU  - Paulovich AG
AD  - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 
      98109, USA.
LA  - eng
GR  - U24 CA210954/CA/NCI NIH HHS/United States
GR  - S10 OD028685/OD/NIH HHS/United States
GR  - R50 CA211499/CA/NCI NIH HHS/United States
GR  - U24 CA210993/CA/NCI NIH HHS/United States
GR  - U01 CA214114/CA/NCI NIH HHS/United States
GR  - P30 CA015083/CA/NCI NIH HHS/United States
GR  - P50 CA136393/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20211221
PL  - United States
TA  - Cell Rep Med
JT  - Cell reports. Medicine
JID - 101766894
RN  - 0 (Fatty Acids)
RN  - 0 (Phosphoproteins)
RN  - 0 (Reactive Oxygen Species)
RN  - BG3F62OND5 (Carboplatin)
RN  - EC 2.3.1.21 (CPT1A protein, human)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 6.4.1.2 (ACACB protein, human)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
SB  - IM
MH  - Acetyl-CoA Carboxylase/genetics/metabolism
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Carboplatin/pharmacology/*therapeutic use
MH  - Carnitine O-Palmitoyltransferase/antagonists & inhibitors/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cystadenocarcinoma, Serous/drug therapy/*metabolism/*pathology
MH  - DNA Damage
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Fatty Acids/metabolism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - *Genomics
MH  - Humans
MH  - Mice, SCID
MH  - *Molecular Targeted Therapy
MH  - Neoplasm Grading
MH  - Ovarian Neoplasms/drug therapy/*metabolism/*pathology
MH  - Oxidation-Reduction/drug effects
MH  - Oxidative Phosphorylation/drug effects
MH  - Phosphoproteins/metabolism
MH  - Proteomics
MH  - Reactive Oxygen Species/metabolism
MH  - Mice
PMC - PMC8714940
OTO - NOTNLM
OT  - CPT1A
OT  - carboplatin
OT  - fatty acid oxidation
OT  - ovarian cancer
OT  - oxidative phosphorylation
OT  - proteogenomic
OT  - proteomic
OT  - reactive oxygen species
OT  - resistance
COIS- 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.
EDAT- 2022/01/15 06:00
MHDA- 2022/03/04 06:00
PMCR- 2021/12/21
CRDT- 2022/01/14 06:09
PHST- 2020/12/18 00:00 [received]
PHST- 2021/09/24 00:00 [revised]
PHST- 2021/11/19 00:00 [accepted]
PHST- 2022/01/14 06:09 [entrez]
PHST- 2022/01/15 06:00 [pubmed]
PHST- 2022/03/04 06:00 [medline]
PHST- 2021/12/21 00:00 [pmc-release]
AID - S2666-3791(21)00343-8 [pii]
AID - 100471 [pii]
AID - 10.1016/j.xcrm.2021.100471 [doi]
PST - epublish
SO  - Cell Rep Med. 2021 Dec 21;2(12):100471. doi: 10.1016/j.xcrm.2021.100471. 
      eCollection 2021 Dec 21.