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.
Highlights
The cyclin-dependent kinases CDK4 and CDK6 are core components of the signal transduction network controlling transition of cells from G1 (Gap1) phase of the cell cycle into S (DNA synthesis) [1, 2]
To assess CDK2 activation in cells exposed to CDK4/6is, we used a cell-based CDK2 reporter (GFP-PSLD) where a green-fluorescent protein (GFP) is fused to the CDK2regulated phosphorylated subcellular localisation domain (PSLD) of human DNA helicase B [25]
Palbociclib treatment increased the percentage of cells with the nuclear-localised CDK2 reporter, a considerable portion of cells with loss of cyclin-dependent kinases 4 and 6 (CDK4/6) activity, detected by the absence of RB1 phosphorylated at the CDK4/6-selective phosphorylation site Ser780 [27], continued to contain a reporter with predominant cytoplasmic localisation (Supplementary Fig. 1d, e)
Summary
The cyclin-dependent kinases CDK4 and CDK6 are core components of the signal transduction network controlling transition of cells from G1 (Gap1) phase of the cell cycle into S (DNA synthesis) [1, 2]. Deregulation of this network is a common event in cancer. Gene mutation of regulators involved in limiting CDK4/6 activation is exceptionally frequent in all types of cancer [3, 4]. Evidence for clinical benefit has not been extended to other cancer types far, and relapse under therapy is frequent in the approved indication in breast cancer [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
