Synthetic lethality guiding selection of drug combinations in ovarian cancer.
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Bevacizumab
/ administration & dosage
Clinical Trials as Topic
Female
Humans
Molecular Targeted Therapy
/ methods
Ovarian Neoplasms
/ drug therapy
Paclitaxel
/ administration & dosage
Phthalazines
/ administration & dosage
Piperazines
/ administration & dosage
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Proto-Oncogene Proteins c-bcl-2
/ antagonists & inhibitors
Synthetic Lethal Mutations
/ drug effects
Vascular Endothelial Growth Factor A
/ antagonists & inhibitors
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
27
02
2018
accepted:
03
01
2019
entrez:
26
1
2019
pubmed:
27
1
2019
medline:
23
10
2019
Statut:
epublish
Résumé
Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy. We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer. Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies. A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.
Sections du résumé
BACKGROUND
Synthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.
MATERIALS AND METHODS
We established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.
RESULTS
Twelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies.
CONCLUSION
A set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.
Identifiants
pubmed: 30682083
doi: 10.1371/journal.pone.0210859
pii: PONE-D-18-06274
pmc: PMC6347359
doi:
Substances chimiques
BCL2 protein, human
0
Phthalazines
0
Piperazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Proto-Oncogene Proteins c-bcl-2
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
Bevacizumab
2S9ZZM9Q9V
Paclitaxel
P88XT4IS4D
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0210859Déclaration de conflit d'intérêts
AL is managing partner of emergentec biodevelopment GmbH, Austria. AH, PP, and PM at the time of performing the analysis were employees of emergentec biodevelopment GmbH. Commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors declare that they have no competing interests.
Références
Nucleic Acids Res. 2014 Jan;42(Database issue):D7-17
pubmed: 24259429
Lancet Oncol. 2015 Jan;16(1):87-97
pubmed: 25481791
Front Oncol. 2013 Mar 20;3:58
pubmed: 23519775
PLoS One. 2008 Jan 23;3(1):e1440
pubmed: 18213364
Nat Rev Cancer. 2011 Sep 23;11(10):719-25
pubmed: 21941283
FEBS Lett. 2011 Jan 3;585(1):1-6
pubmed: 21094158
Ann Oncol. 2014 Jan;25(1):160-5
pubmed: 24318743
Ther Adv Med Oncol. 2016 May;8(3):188-97
pubmed: 27239237
Invest New Drugs. 2016 Feb;34(1):119-28
pubmed: 26643663
Int Immunopharmacol. 2011 Feb;11(2):212-9
pubmed: 21115120
Nucleic Acids Res. 2012 Jan;40(Database issue):D306-12
pubmed: 22096229
J Mol Biol. 2001 Dec 14;314(5):1041-52
pubmed: 11743721
Science. 1997 Nov 7;278(5340):1064-8
pubmed: 9353181
Science. 2010 Jan 22;327(5964):425-31
pubmed: 20093466
Cell Oncol (Dordr). 2015 Apr;38(2):155-64
pubmed: 25539992
Bioinformatics. 2012 Mar 1;28(5):715-6
pubmed: 22247275
Nucleic Acids Res. 2014 Jan;42(Database issue):D199-205
pubmed: 24214961
Oncotarget. 2016 Jan 26;7(4):4167-82
pubmed: 26716409
Nucleic Acids Res. 2011 Jan;39(Database issue):D289-94
pubmed: 21113020
Nature. 2005 Apr 14;434(7035):917-21
pubmed: 15829967
Ann Oncol. 2007 Sep;18(9):1529-38
pubmed: 17761710
Oncotarget. 2018 Nov 20;9(91):36379-36391
pubmed: 30555636
Nat Med. 2015 Nov;21(11):1318-25
pubmed: 26479923
Clin Cancer Res. 2008 Dec 1;14(23):7917-23
pubmed: 19047122
Lancet Oncol. 2015 Aug;16(8):928-36
pubmed: 26115797
Nature. 2005 Apr 14;434(7035):913-7
pubmed: 15829966
Genetics. 1946 May;31:269-90
pubmed: 20985721
Immunome Res. 2008 Jan 07;4:1
pubmed: 18179690
J Clin Pharmacol. 2016 Nov;56(11):1387-1394
pubmed: 27093880
Cell. 2012 May 11;149(4):780-94
pubmed: 22579283
Nat Chem Biol. 2017 Jan;13(1):12-14
pubmed: 27820796
BMC Syst Biol. 2016 Apr 18;10:33
pubmed: 27090655
Gynecol Oncol. 2016 Aug;142(2):323-31
pubmed: 27282964
Clin Cancer Res. 2015 Oct 1;21(19):4257-61
pubmed: 26187614
Clin Breast Cancer. 2014 Jun;14(3):161-8
pubmed: 24566467
Gynecol Oncol. 2015 Dec;139(3):413-8
pubmed: 26144600
Cancer Res. 2012 Aug 15;72(16):4193-203
pubmed: 22689920
Contemp Oncol (Pozn). 2016;20(1):28-32
pubmed: 27095936
Nat Rev Cancer. 2017 Apr;17(4):254-268
pubmed: 28104906
Nat Rev Cancer. 2016 Feb;16(2):110-20
pubmed: 26775620
Nucleic Acids Res. 2014 Jan;42(Database issue):D546-52
pubmed: 24163254
Gynecol Oncol. 2011 May 1;121(2):353-7
pubmed: 21324516
Mol Biosyst. 2012 Oct 30;8(12):3197-207
pubmed: 23014771
Genome Res. 2003 Sep;13(9):2129-41
pubmed: 12952881
Mol Biosyst. 2011 Jan;7(1):200-14
pubmed: 21031175
Target Oncol. 2015 Dec;10(4):575-81
pubmed: 25940934