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Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor
Cancer Cell ( IF 48.8 ) Pub Date : 2021-09-13 , DOI: 10.1016/j.ccell.2021.08.009
Kevin Freeman-Cook 1 , Robert L Hoffman 1 , Nichol Miller 1 , Jonathan Almaden 1 , John Chionis 1 , Qin Zhang 1 , Koleen Eisele 1 , Chaoting Liu 1 , Cathy Zhang 1 , Nanni Huser 1 , Lisa Nguyen 1 , Cinthia Costa-Jones 1 , Sherry Niessen 1 , Jordan Carelli 1 , John Lapek 1 , Scott L Weinrich 1 , Ping Wei 1 , Elizabeth McMillan 1 , Elizabeth Wilson 1 , Tim S Wang 1 , Michele McTigue 1 , Rose Ann Ferre 1 , You-Ai He 1 , Sacha Ninkovic 1 , Douglas Behenna 1 , Khanh T Tran 1 , Scott Sutton 1 , Asako Nagata 1 , Martha A Ornelas 1 , Susan E Kephart 1 , Luke R Zehnder 1 , Brion Murray 1 , Meirong Xu 1 , James E Solowiej 1 , Ravi Visswanathan 1 , Britton Boras 1 , David Looper 1 , Nathan Lee 1 , Jadwiga R Bienkowska 1 , Zhou Zhu 1 , Zhengyan Kan 1 , Ying Ding 1 , Xinmeng Jasmine Mu 1 , Cecilia Oderup 1 , Shahram Salek-Ardakani 1 , Michael A White 1 , Todd VanArsdale 1 , Stephen G Dann 1
Affiliation  

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.



中文翻译:

使用 CDK2/4/6 抑制剂扩大对肿瘤细胞周期的控制

CDK4/6 抑制剂 palbociclib (PAL)与抗激素药物联合使用时,可显着提高 HR + /HER2 -乳腺癌的无进展生存期。我们试图通过临床前模型和临床转录组样本的分析来发现 PAL 耐药机制,这些机制在MYC癌基因和细胞周期蛋白 E/CDK2 活性的诱导上结合。我们建议用小分子靶向 G 1激酶 CDK2、CDK4 和 CDK6 克服对 CDK4/6 抑制的抵抗。我们描述了 PF-06873600 (PF3600) 的药效学和功效,PF-06873600 是一种吡啶并嘧啶,可在多种体内肿瘤模型中有效抑制 CDK2/4/6 的活性和功效。连同临床分析,MYC活性预测 (PF3600) 跨多个细胞谱系的功效。最后,我们发现 CDK2/4/6 抑制不会损害同基因模型中的肿瘤特异性免疫检查点阻断反应。我们预计目前处于 1 期临床试验的 (PF3600) 为 CDK4/6 抑制不足以改变疾病进展的癌症患者提供治疗选择。

更新日期:2021-10-11
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