dc.contributor.author | Zhang, C | |
dc.contributor.author | Stockwell, SR | |
dc.contributor.author | Elbanna, M | |
dc.contributor.author | Ketteler, R | |
dc.contributor.author | Freeman, J | |
dc.contributor.author | Al-Lazikani, B | |
dc.contributor.author | Eccles, S | |
dc.contributor.author | De Haven Brandon, A | |
dc.contributor.author | Raynaud, F | |
dc.contributor.author | Hayes, A | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Mittnacht, S | |
dc.date.accessioned | 2020-06-03T11:36:18Z | |
dc.date.issued | 2019-07-25 | |
dc.identifier.citation | Oncogene, 2019, 38 (30), pp. 5905 - 5920 | |
dc.identifier.issn | 0950-9232 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3687 | |
dc.identifier.eissn | 1476-5594 | |
dc.identifier.doi | 10.1038/s41388-019-0850-2 | |
dc.description.abstract | Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these kinases are currently used only in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and the mechanisms that may undermine such dependency are poorly understood. Here, we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss of the CDKI p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates the proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic. | |
dc.format | Print-Electronic | |
dc.format.extent | 5905 - 5920 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Cell Cycle | |
dc.subject | Cell Division | |
dc.subject | Proto-Oncogene Proteins c-met | |
dc.subject | Cyclin-Dependent Kinase 2 | |
dc.subject | Cyclin-Dependent Kinase 4 | |
dc.subject | Cyclin-Dependent Kinase 6 | |
dc.subject | Focal Adhesion Protein-Tyrosine Kinases | |
dc.subject | Heterografts | |
dc.subject | Biomarkers, Tumor | |
dc.subject | A549 Cells | |
dc.title | Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-05-13 | |
rioxxterms.versionofrecord | 10.1038/s41388-019-0850-2 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-07-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncogene | |
pubs.issue | 30 | |
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/Computational Biology and Chemogenomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
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/Computational Biology and Chemogenomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.publication-status | Published | |
pubs.volume | 38 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group) | |
icr.researchteam | Computational Biology and Chemogenomics | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
dc.contributor.icrauthor | Zhang, Chi | |
dc.contributor.icrauthor | Al-Lazikani, Bissan | |
dc.contributor.icrauthor | Raynaud, Florence | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Workman, Paul | |