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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.issued2020-08-18
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.publisherSPRINGERNATURE
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.volume123
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
icr.researchteamMolecular Addictions
icr.researchteamSystems and Precision Cancer Medicine
dc.contributor.icrauthorHeuss, Sara Farrah
dc.contributor.icrauthorHussain, Aasia
dc.contributor.icrauthorRaynaud, Florence
dc.contributor.icrauthorChung, Yuen-Li
dc.contributor.icrauthorVivanco, Igor


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