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Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases.

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Zhang, Chi 
Stockwell, Simon R 
Elbanna, May 
Ketteler, Robin 
Freeman, Jamie 


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.



A549 Cells, Animals, Biomarkers, Tumor, Cell Cycle, Cell Division, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Focal Adhesion Protein-Tyrosine Kinases, Heterografts, Humans, Mice, Proto-Oncogene Mas, Proto-Oncogene Proteins c-met

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Springer Nature
The work was supported by grants from Cancer Research UK (ref. C309/A11566, ref. C309/A8274 and ref. C309/A8992 (PW), ref. C423/A1421 and ref. C423/A15043 (SM)) and the World Cancer Research Fund (WCRF) (ref. 12-1280). CZ was supported by a Wellcome Trust studentship (ref. 094885/Z/10/Z).