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bioRxiv · 10.1101/601799

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

Zhang, C.·Stockwell, S. R.·Elbanna, M.·Ketteler, R.·Freeman, J.·Al-Lazikani, B.·Eccles, S.·De Haven Brandon, A.·Raynaud, F.·Hayes, A.·Clarke, P. A.·Workman, P.·Mittnacht, S.
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Abstract

Deregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer yet inhibitors against these kinases currently show use in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and what may undermine such dependency is 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 a critical mechanistic events loss of the CDK inhibitor p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates 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.

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Zhang, C., Stockwell, S. R., Elbanna, M., Ketteler, R., Freeman, J., Al-Lazikani, B., Eccles, S., De Haven Brandon, A., Raynaud, F., Hayes, A., Clarke, P. A., Workman, P., Mittnacht, S.. 2019-04-08. Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases. https://doi.org/10.1101/601799

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