Oncology Research & Development, Pfizer Worldwide Research and Development , Pearl River, NY, USA.
Cell Cycle. 2021 Jan;20(1):65-80. doi: 10.1080/15384101.2020.1859195. Epub 2020 Dec 28.
Palbociclib, a selective CDK4/6 kinase inhibitor, is approved in combination with endocrine therapies for the treatment of advanced estrogen receptor positive (ER+) breast cancer. In pre-clinical cancer models, CDK4/6 inhibitors act primarily as cytostatic agents. In two commonly studied ER+ breast cancer cell lines (MCF7 and T47D), CDK4/6 inhibition drives G1-phase arrest and the acquisition of a senescent-like phenotype, both of which are reversible upon palbociclib withdrawal (incomplete senescence). Here we identify an ER+ breast cancer cell line, CAMA1, in which palbociclib treatment induces irreversible cell cycle arrest and senescence (complete senescence). In stark contrast to T47D and MCF7 cells, mTORC1 activity is not stably suppressed in CAMA1 cells during palbociclib treatment. Importantly, inhibition of mTORC1 signaling either by the mTORC1 inhibitor rapamycin or by knockdown of Raptor, a unique component of mTORC1, during palbociclib treatment of CAMA1 cells blocks the induction of complete senescence. These results indicate that sustained mTORC1 activity promotes complete senescence in ER+ breast cancer cells during CDK4/6 inhibitor-induced cell cycle arrest. Consistent with this mechanism, genetic depletion of TSC2, a negative regulator of mTORC1, in MCF7 cells resulted in sustained mTORC1 activity during palbociclib treatment and evoked a complete senescence response. These findings demonstrate that persistent mTORC1 signaling during palbociclib-induced G1 arrest is a potential liability for ER+ breast cancer cells, and suggest a strategy for novel drug combinations with palbociclib.
帕博西尼（Palbociclib），一种选择性 CDK4/6 激酶抑制剂，与内分泌疗法联合用于治疗晚期雌激素受体阳性（ER+）乳腺癌。在临床前癌症模型中，CDK4/6 抑制剂主要作为细胞周期停滞剂发挥作用。在两种常用的 ER+乳腺癌细胞系（MCF7 和 T47D）中，CDK4/6 抑制导致 G1 期停滞和获得衰老样表型，这两种表型在帕博西尼停药后均可逆转（不完全衰老）。在这里，我们鉴定了一种 ER+乳腺癌细胞系 CAMA1，其中帕博西尼治疗诱导不可逆的细胞周期停滞和衰老（完全衰老）。与 T47D 和 MCF7 细胞形成鲜明对比的是，在帕博西尼治疗期间，CAMA1 细胞中的 mTORC1 活性并没有被稳定抑制。重要的是，在 CAMA1 细胞中用 mTORC1 抑制剂雷帕霉素或通过敲低 Raptor（mTORC1 的独特组成部分）抑制 mTORC1 信号，在帕博西尼治疗期间阻断完全衰老的诱导。这些结果表明，在 CDK4/6 抑制剂诱导的细胞周期停滞期间，持续的 mTORC1 活性促进 ER+乳腺癌细胞中的完全衰老。与该机制一致，在 MCF7 细胞中遗传耗尽 TSC2（mTORC1 的负调节剂）导致在帕博西尼治疗期间持续的 mTORC1 活性，并引发完全衰老反应。这些发现表明，在帕博西尼诱导的 G1 期停滞期间持续的 mTORC1 信号是 ER+乳腺癌细胞的潜在缺陷，并为与帕博西尼联合使用新型药物组合提供了策略。
