Inferring tumor-specific cancer dependencies through integrating ex vivo drug response assays and drug-protein profiling.
Journal
PLoS computational biology
ISSN: 1553-7358
Titre abrégé: PLoS Comput Biol
Pays: United States
ID NLM: 101238922
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
18
04
2022
accepted:
26
07
2022
revised:
01
09
2022
pubmed:
23
8
2022
medline:
9
9
2022
entrez:
22
8
2022
Statut:
epublish
Résumé
The development of cancer therapies may be improved by the discovery of tumor-specific molecular dependencies. The requisite tools include genetic and chemical perturbations, each with its strengths and limitations. Chemical perturbations can be readily applied to primary cancer samples at large scale, but mechanistic understanding of hits and further pharmaceutical development is often complicated by the fact that a chemical compound has affinities to multiple proteins. To computationally infer specific molecular dependencies of individual cancers from their ex vivo drug sensitivity profiles, we developed a mathematical model that deconvolutes these data using measurements of protein-drug affinity profiles. Through integrating a drug-kinase profiling dataset and several drug response datasets, our method, DepInfeR, correctly identified known protein kinase dependencies, including the EGFR dependence of HER2+ breast cancer cell lines, the FLT3 dependence of acute myeloid leukemia (AML) with FLT3-ITD mutations and the differential dependencies on the B-cell receptor pathway in the two major subtypes of chronic lymphocytic leukemia (CLL). Furthermore, our method uncovered new subgroup-specific dependencies, including a previously unreported dependence of high-risk CLL on Checkpoint kinase 1 (CHEK1). The method also produced a detailed map of the kinase dependencies in a heterogeneous set of 117 CLL samples. The ability to deconvolute polypharmacological phenotypes into underlying causal molecular dependencies should increase the utility of high-throughput drug response assays for functional precision oncology.
Identifiants
pubmed: 35994503
doi: 10.1371/journal.pcbi.1010438
pii: PCOMPBIOL-D-22-00597
pmc: PMC9436053
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Receptors, Antigen, B-Cell
0
Protein Kinases
EC 2.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010438Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Stat Softw. 2010;33(1):1-22
pubmed: 20808728
Comput Struct Biotechnol J. 2020 Nov 24;18:3819-3832
pubmed: 33335681
Nat Commun. 2017 May 05;8:15178
pubmed: 28474669
Genome Biol. 2014;15(12):550
pubmed: 25516281
Pharmacogenomics. 2016 May;17(7):691-700
pubmed: 27180993
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Nature. 2018 Oct;562(7728):526-531
pubmed: 30333627
Nucleic Acids Res. 2013 Jan;41(Database issue):D955-61
pubmed: 23180760
Clin Cancer Res. 2011 Nov 15;17(22):7067-79
pubmed: 21933891
Nat Rev Cancer. 2010 Jan;10(1):37-50
pubmed: 19956173
Cancer Discov. 2016 Aug;6(8):900-13
pubmed: 27260157
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
Cancer Res. 2007 Jul 15;67(14):6574-81
pubmed: 17638866
Science. 2017 Dec 1;358(6367):
pubmed: 29191878
Cancer Discov. 2019 Aug;9(8):1050-1063
pubmed: 31088841
Leukemia. 2019 Feb;33(2):299-312
pubmed: 30651634
Nat Chem Biol. 2007 Dec;3(12):739-44
pubmed: 18007642
Mol Syst Biol. 2020 Jul;16(7):e9405
pubmed: 32627965
Science. 1987 Jan 9;235(4785):177-82
pubmed: 3798106
Blood. 1999 Sep 15;94(6):1840-7
pubmed: 10477712
Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):459-64
pubmed: 23267079
J Clin Invest. 2018 Jan 2;128(1):427-445
pubmed: 29227286
Leuk Lymphoma. 2010 May;51(5):881-91
pubmed: 20367563
Nat Rev Drug Discov. 2017 Feb;16(2):89-100
pubmed: 28008168
Nat Commun. 2018 Nov 2;9(1):4610
pubmed: 30389920
N Engl J Med. 2000 Dec 28;343(26):1910-6
pubmed: 11136261
Oncotarget. 2016 Jan 26;7(4):4598-610
pubmed: 26717038
J Cancer. 2017 Sep 12;8(16):3131-3141
pubmed: 29158785
Oncotarget. 2016 Nov 22;7(47):77163-77174
pubmed: 27791198
Methods Mol Biol. 2019;1961:127-134
pubmed: 30912044
Nucleic Acids Res. 2015 Apr 20;43(7):e47
pubmed: 25605792
Nature. 2019 Apr;568(7753):511-516
pubmed: 30971826
Cell Death Differ. 2019 Dec;26(12):2551-2567
pubmed: 30894677
Bioinformatics. 2012 Jan 1;28(1):112-8
pubmed: 22039212
Exp Hematol. 2016 Jul;44(7):603-13
pubmed: 27181063
J Cell Sci. 2013 Oct 15;126(Pt 20):4746-55
pubmed: 23943874
Nat Cancer. 2021 Aug;2(8):853-864
pubmed: 34423310
J Pathol Transl Med. 2020 Jan;54(1):34-44
pubmed: 31693827
Oncogene. 2012 Mar 29;31(13):1661-72
pubmed: 21841818
Genome Res. 2014 Feb;24(2):212-26
pubmed: 24265505
Breast Cancer (Dove Med Press). 2017 Mar 21;9:185-198
pubmed: 28356768
Mol Cell. 2018 Mar 15;69(6):1017-1027.e6
pubmed: 29526696
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Sci Rep. 2017 Oct 23;7(1):13734
pubmed: 29062038
Oncogene. 2000 Nov 20;19(49):5590-7
pubmed: 11114739
Nat Commun. 2017 Nov 22;8(1):1697
pubmed: 29167438
Front Oncol. 2014 Sep 23;4:263
pubmed: 25295230
Nat Rev Drug Discov. 2021 Nov;20(11):839-861
pubmed: 34354255
Nat Rev Cancer. 2014 Apr;14(4):219-32
pubmed: 24658273
Sci Data. 2014 Sep 30;1:140035
pubmed: 25984343
Cell Stem Cell. 2014 Nov 6;15(5):643-52
pubmed: 25517468
Blood. 2004 May 1;103(9):3544-6
pubmed: 14670924
Drug Discov Today Technol. 2015 Nov;18:1-8
pubmed: 26723886
Nat Rev Drug Discov. 2008 May;7(5):391-7
pubmed: 18404149
Cell. 2016 Jul 28;166(3):740-754
pubmed: 27397505