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Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. | LitMetric

AI Article Synopsis

  • Palbociclib (PAL) is a CDK4/6 inhibitor that improves survival in HR/HER2 breast cancer when paired with hormonal therapies, but resistance mechanisms were investigated.
  • Researchers identified that the MYC oncogene and Cyclin E/CDK2 activity contribute to this resistance, suggesting that targeting CDK2 along with CDK4/6 could be a solution.
  • PF-06873600 (PF3600), a new drug inhibiting CDK2/4/6, shows promise in early trials and maintains effectiveness alongside immune checkpoint treatments, potentially aiding patients resistant to PAL.

Article Abstract

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 G 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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Source
http://dx.doi.org/10.1016/j.ccell.2021.08.009DOI Listing

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