dc.contributor.author | Kostaras, E | |
dc.contributor.author | Kaserer, T | |
dc.contributor.author | Lazaro, G | |
dc.contributor.author | Heuss, SF | |
dc.contributor.author | Hussain, A | |
dc.contributor.author | Casado, P | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Yandim, C | |
dc.contributor.author | Palaskas, N | |
dc.contributor.author | Yu, Y | |
dc.contributor.author | Schwartz, B | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Chung, Y-L | |
dc.contributor.author | Cutillas, PR | |
dc.contributor.author | Vivanco, I | |
dc.date.accessioned | 2020-06-02T09:14:39Z | |
dc.date.issued | 2020-08-18 | |
dc.identifier.citation | British journal of cancer, 2020, 123 (4), pp. 542 - 555 | |
dc.identifier.issn | 0007-0920 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3667 | |
dc.identifier.eissn | 1532-1827 | |
dc.identifier.doi | 10.1038/s41416-020-0889-4 | |
dc.description.abstract | BACKGROUND: 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.format | Print-Electronic | |
dc.format.extent | 542 - 555 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | SPRINGERNATURE | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-04-24 | |
rioxxterms.versionofrecord | 10.1038/s41416-020-0889-4 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | British journal of cancer | |
pubs.issue | 4 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 123 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Molecular Addictions | |
icr.researchteam | Systems and Precision Cancer Medicine | |
dc.contributor.icrauthor | Heuss, Sara Farrah | |
dc.contributor.icrauthor | Hussain, Aasia | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Chung, Yuen-Li | |
dc.contributor.icrauthor | Vivanco, Igor | |