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Publication : Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.

First Author  Freeman-Cook K Year  2021
Journal  Cancer Cell Volume  39
Issue  10 Pages  1404-1421.e11
PubMed ID  34520734 Mgi Jnum  J:355252
Mgi Id  MGI:6780650 Doi  10.1016/j.ccell.2021.08.009
Citation  Freeman-Cook K, et al. (2021) Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell 39(10):1404-1421.e11
abstractText  The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR(+)/HER2(-) breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
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