Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.
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Authors
Zhang, C
Stockwell, SR
Elbanna, M
Ketteler, R
Freeman, J
Al-Lazikani, B
Eccles, S
De Haven Brandon, A
Raynaud, F
Hayes, A
Clarke, PA
Workman, P
Mittnacht, S
Stockwell, SR
Elbanna, M
Ketteler, R
Freeman, J
Al-Lazikani, B
Eccles, S
De Haven Brandon, A
Raynaud, F
Hayes, A
Clarke, PA
Workman, P
Mittnacht, S
Document Type
Journal Article
Date
2019-07-25
Date Accepted
2019-05-13
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.
Citation
Oncogene, 2019, 38 (30), pp. 5905 - 5920
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0950-9232
eISSN
1476-5594
Collections
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Computational Biology and Chemogenomics
Signal Transduction & Molecular Pharmacology
Computational Biology and Chemogenomics
Signal Transduction & Molecular Pharmacology