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

摘要: Deregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer; yet, inhibitors against these are currently used only restricted tumour contexts. The extent to which cancers depend on CDK4/6 the mechanisms that may undermine such dependency poorly understood. Here, we report signalling engaging MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads CDK4/6-independent CDK2 activation, involving as critical mechanistic events loss CDKI p21CIP1 gain its regulator, ubiquitin ligase subunit SKP2. Combined inhibition MET/FAK eliminates proliferation capacity cancer cells culture, enhances growth vivo. Activation known arise through extrinsic intrinsic cues. Our work predicts cues support cell division independent activity cycle-regulating identifies a tractable route broaden utility inhibitor-based therapies clinic.