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dc.contributor.authorKostaras, E
dc.contributor.authorKaserer, T
dc.contributor.authorLazaro, G
dc.contributor.authorHeuss, SF
dc.contributor.authorHussain, A
dc.contributor.authorCasado, P
dc.contributor.authorHayes, A
dc.contributor.authorYandim, C
dc.contributor.authorPalaskas, N
dc.contributor.authorYu, Y
dc.contributor.authorSchwartz, B
dc.contributor.authorRaynaud, F
dc.contributor.authorChung, Y-L
dc.contributor.authorCutillas, PR
dc.contributor.authorVivanco, I
dc.date.accessioned2020-06-02T09:14:39Z
dc.date.issued2020-08
dc.identifier.citationBritish journal of cancer, 2020, 123 (4), pp. 542 - 555
dc.identifier.issn0007-0920
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3667
dc.identifier.eissn1532-1827
dc.identifier.doi10.1038/s41416-020-0889-4
dc.description.abstractBackground AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants.Methods We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity.Results Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations.Conclusions These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.
dc.formatPrint-Electronic
dc.format.extent542 - 555
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleA systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.
dc.typeJournal Article
dcterms.dateAccepted2020-04-24
rioxxterms.versionofrecord10.1038/s41416-020-0889-4
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-08
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBritish journal of cancer
pubs.issue4
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Addictions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Molecular Addictions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.publication-statusPublished
pubs.volume123en_US
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMolecular Addictionsen_US
icr.researchteamSystems and Precision Cancer Medicineen_US
dc.contributor.icrauthorVivanco, Igoren
dc.contributor.icrauthorRaynaud, Florenceen
dc.contributor.icrauthorHussain, Aasiaen
dc.contributor.icrauthorChung, Yuen-Lien


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