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