Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth.
Stromal Senescence By Prolonged CDK4/6 Inhibition Potentiates Tumor Growth.
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DOI：
10.1158/1541-7786.mcr-16-0319
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Burd CE
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文献类型：
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作者：
Guan X;LaPak KM;Hennessey RC;Yu CY;Shakya R;Zhang J;Burd CE
肿瘤微环境（TME）内的衰老细胞采用促炎、衰老相关的分泌表型（SASP），促进癌症的发生、进展和治疗耐药。在这里，暴露于 CDK4/6 抑制剂 Palbociclib (PD-0332991) 会诱导正常成纤维细胞衰老和增强 SASP。长期抑制 CDK4/6 引起的衰老与 DNA 损伤无关，并且与 Mdm2 下调相关，而这些细胞引发的 SASP 在很大程度上依赖于 NF-κB 激活。基于这些观察结果，假设未转化的基质细胞暴露于 PD-0332991 会促进肿瘤生长。正在进行的 CDK4/6 抑制剂治疗黑色素瘤的临床试验促使使用一套基因定义的黑色素瘤细胞（即 Ras 突变体、Braf 突变体和 Ras/Braf 野生型）验证了这一假设。当在 CDK4/6i 诱导的衰老成纤维细胞存在的情况下培养时，黑色素瘤细胞系表现出基因型依赖性增殖反应。然而，在体内，PD-0332991 处理的成纤维细胞增强了所有测试的黑色素瘤系的生长，并促进了 Gr-1 阳性免疫细胞的募集。这些数据表明，长期 CDK4/6 抑制剂治疗会导致正常成纤维细胞进入衰老状态并形成强大的 SASP。在免疫活性强的体内模型中，这种衰老细胞抑制抗肿瘤免疫反应并促进黑色素瘤生长。延长 CDK4/6 抑制剂治疗诱导细胞衰老和原代细胞中强大的 SASP 的能力可能会阻碍治疗效果并促进长期的老年性后果，在旨在治疗黑色素瘤和其他癌症类型的临床试验中应考虑这一点。
Senescent cells within the tumor microenvironment (TME) adopt a pro-inflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression and therapeutic resistance. Here, exposure to Palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation. Based upon these observations, it was hypothesized that the exposure of non-transformed stromal cells to PD-0332991 would promote tumor growth. Ongoing clinical trials of CDK4/6 inhibitors in melanoma prompted a validation of this hypothesis using a suite of genetically defined melanoma cells (i.e. Ras mutant, Braf mutant, and Ras/Braf wild type). When cultured in the presence of CDK4/6i–induced senescent fibroblasts, melanoma cell lines exhibited genotype-dependent proliferative responses. However, in vivo, PD-0332991-treated fibroblasts enhanced the growth of all melanoma lines tested and promoted the recruitment of Gr-1-positive immune cells. These data indicate that prolonged CDK4/6 inhibitor treatment causes normal fibroblasts to enter senescence and adopt a robust SASP. Such senescent cells suppress the anti-tumor immune response and promote melanoma growth in immunocompetent, in vivo models. The ability of prolonged CDK4/6 inhibitor treatment to induce cellular senescence and a robust SASP in primary cells may hinder therapeutic efficacy and promote long-term, gerontogenic consequences that should be considered in clinical trials aiming to treat melanoma and other cancer types.