The cyclin dependent kinase (CDK)–retinoblastoma (RB)–E2F pathway plays a critical role in the control of cell cycle in estrogen receptor–positive (ER+) breast cancer. Small-molecule inhibitors of CDK4/6 have shown promise in this tumor type in combination with hormonal therapies, reflecting the particular dependence of this subtype of cancer on cyclin D1 and E2F transcription factors. mTOR inhibitors have also shown potential in clinical trials in this disease setting. Recent data have suggested cooperation between the PI3K/mTOR pathway and CDK4/6 inhibition in preventing early adaptation and eliciting growth arrest, but the mechanisms of the interplay between these pathways have not been fully elucidated. Here we show that profound and durable inhibition of ER+ breast cancer growth is likely to require multiple hits on E2F-mediated transcription. We demonstrate that inhibition of mTORC1/2 does not affect ER function directly, but does cause a decrease in cyclin D1 protein, RB phosphorylation, and E2F-mediated transcription. Combination of an mTORC1/2 inhibitor with a CDK4/6 inhibitor results in more profound effects on E2F-dependent transcription, which translates into more durable growth arrest and a delay in the onset of resistance. Combined inhibition of mTORC1/2, CDK4/6, and ER delivers even more profound and durable regressions in breast cancer cell lines and xenografts. Furthermore, we show that CDK4/6 inhibitor–resistant cell lines reactivate the CDK–RB–E2F pathway, but remain sensitive to mTORC1/2 inhibition, suggesting that mTORC1/2 inhibitors may represent an option for patients that have relapsed on CDK4/6 therapy. Mol Cancer Ther; 17(5); 908–20. ©2018 AACR.

中文翻译：

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雌激素受体阳性乳腺癌中，需要联合抑制 mTOR 和 CDK4/6，以实现 E2F 功能的最佳阻断和长期生长抑制


细胞周期蛋白依赖性激酶 (CDK)-视网膜母细胞瘤 (RB)-E2F 通路在雌激素受体阳性 (ER+) 乳腺癌细胞周期的控制中发挥着关键作用。 CDK4/6 小分子抑制剂与激素疗法相结合，在这种肿瘤类型中显示出良好的前景，反映了这种癌症亚型对细胞周期蛋白 D1 和 E2F 转录因子的特殊依赖性。 mTOR 抑制剂在这种疾病的临床试验中也显示出了潜力。最近的数据表明 PI3K/mTOR 通路和 CDK4/6 抑制之间的合作可以防止早期适应和引起生长停滞，但这些通路之间相互作用的机制尚未完全阐明。在这里，我们表明，对 ER+ 乳腺癌生长的深刻而持久的抑制可能需要对 E2F 介导的转录进行多次打击。我们证明，抑制 mTORC1/2 不会直接影响 ER 功能，但会导致细胞周期蛋白 D1 蛋白、RB 磷酸化和 E2F 介导的转录减少。 mTORC1/2 抑制剂与 CDK4/6 抑制剂的组合会对 E2F 依赖性转录产生更深远的影响，从而转化为更持久的生长停滞和延迟耐药性的发生。 mTORC1/2、CDK4/6 和 ER 的联合抑制可在乳腺癌细胞系和异种移植物中提供更深刻、更持久的消退。此外，我们发现 CDK4/6 抑制剂耐药细胞系重新激活 CDK-RB-E2F 通路，但对 mTORC1/2 抑制仍然敏感，这表明 mTORC1/2 抑制剂可能是 CDK4/6 复发患者的一种选择治疗。摩尔癌症治疗； 17(5)； 908–20。 ©2018 AACR。