@article{e9a1b12cd3c8495c8cb509a91b994066,
title = "Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases",
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.",
author = "Chi Zhang and Stockwell, {Simon R.} and May Elbanna and Robin Ketteler and Jamie Freeman and Bissan Al-Lazikani and Suzanne Eccles and {De Haven Brandon}, Alexis and Florence Raynaud and Angela Hayes and Clarke, {Paul A.} and Paul Workman and Sibylle Mittnacht",
note = "Funding Information: Acknowledgements The authors thank Nicky Evans for editorial help with writing this paper, and Albert Hallsworth, Melanie Valenti and Gary Box for assisting with the mouse work. We thank the Vogelstein laboratory for providing isogenic TP53–/–and TP53WTHCT116 human colorectal cancer cells. Financial support: 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). PW is a Cancer Research UK Life Fellow. The funders had no role in the design of the study, the collection, analysis and interpretation of the data, the writing of the paper or the decision to submit the paper for publication. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = jul,
day = "25",
doi = "10.1038/s41388-019-0850-2",
language = "English (US)",
volume = "38",
pages = "5905--5920",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "30",
}