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.

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。