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

Kevin Freeman-Cook, Robert L. Hoffman, Nichol Miller, Jonathan Almaden, John Chionis, Qin Zhang, Koleen Eisele, Chaoting Liu, Cathy Zhang, Nanni Huser, Lisa Nguyen, Cinthia Costa-Jones, Sherry Niessen, Jordan Carelli, John Lapek, Scott L. Weinrich, Ping Wei, Elizabeth McMillan, Elizabeth Wilson, Tim S. WangMichele McTigue, Rose Ann Ferre, You Ai He, Sacha Ninkovic, Douglas Behenna, Khanh T. Tran, Scott Sutton, Asako Nagata, Martha A. Ornelas, Susan E. Kephart, Luke R. Zehnder, Brion Murray, Meirong Xu, James E. Solowiej, Ravi Visswanathan, Britton Boras, David Looper, Nathan Lee, Jadwiga R. Bienkowska, Zhou Zhu, Zhengyan Kan, Ying Ding, Xinmeng Jasmine Mu, Cecilia Oderup, Shahram Salek-Ardakani, Michael A. White, Todd VanArsdale, Stephen G. Dann

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1404-1421.e11
JournalCancer Cell
Volume39
Issue number10
DOIs
StatePublished - Oct 11 2021
Externally publishedYes

Keywords

  • CCNE1
  • CDK2
  • CDK4
  • CDK6
  • MYC
  • cell cycle
  • hormone-receptor-positive breast cancer
  • innate immune response
  • palbociclib
  • therapy resistance

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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