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 language | English (US) |
---|---|
Pages (from-to) | 1404-1421.e11 |
Journal | Cancer Cell |
Volume | 39 |
Issue number | 10 |
DOIs | |
State | Published - Oct 11 2021 |
Externally published | Yes |
Keywords
- CCNE1
- CDK2
- CDK4
- CDK6
- MYC
- cell cycle
- hormone-receptor-positive breast cancer
- innate immune response
- palbociclib
- therapy resistance
ASJC Scopus subject areas
- Oncology
- Cancer Research