CDK5 Inhibition Abrogates TNBC Stem‐Cell Property and Enhances Anti‐PD‐1 Therapy,Advanced Science

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CDK5 Inhibition Abrogates TNBC Stem‐Cell Property and Enhances Anti‐PD‐1 Therapy
Advanced Science ( IF 14.3 ) Pub Date : 2020-10-15 , DOI: 10.1002/advs.202001417
Yuncheng Bei ₁ , Nan Cheng ₁ , Ting Chen _{1,

2} , Yuxin Shu ₁ , Ye Yang ₃ , Nanfei Yang ₁ , Xinyu Zhou ₄ , Baorui Liu ₅ , Jia Wei ₅ , Qin Liu ₅ , Wei Zheng ₁ , Wenlong Zhang ₁ , Huifang Su ₁ , Wei-Guo Zhu ₆ , Jianguo Ji ₄ , Pingping Shen _{1,

6}

Affiliation

Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, in which the higher frequency of cancer stem cells (CSCs) correlates with the poor clinical outcome. An aberrant activation of CDK5 is found to associate with TNBC progression closely. CDK5 mediates PPARγ phosphorylation at its Ser 273, which induces CD44 isoform switching from CD44s to CD44v, resulting in an increase of stemness of TNBC cells. Blocking CDK5/pho‐PPARγ significantly reduces CD44v+ BCSCs population in tumor tissues, thus abrogating metastatic progression in TNBC mouse model. Strikingly, diminishing stemness transformation reverses immunosuppressive microenvironment and enhances anti‐PD‐1 therapeutic efficacy on TNBC. Mechanistically, CDK5 switches the E3 ubiquitin ligase activity of PPARγ and directly protects ESRP1 from a ubiquitin‐dependent proteolysis. This finding firstly indicates that CDK5 blockade can be a potent strategy to diminish stemness transformation and increase the response to PD‐1 blockade in TNBC therapy.

中文翻译：

CDK5 抑制消除 TNBC 干细胞特性并增强抗 PD-1 治疗

三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，其中癌症干细胞（CSC）的较高频率与较差的临床结果相关。研究发现 CDK5 的异常激活与 TNBC 的进展密切相关。CDK5 介导 PPAR γ在其 Ser 273 处磷酸化，从而诱导 CD44 同工型从 CD44s 转换为 CD44v，从而增加 TNBC 细胞的干性。阻断 CDK5/pho-PPAR γ显着减少肿瘤组织中的 CD44v+ BCSC 数量，从而消除 TNBC 小鼠模型中的转移进展。引人注目的是，减少干性转化可逆转免疫抑制微环境并增强抗 PD-1 对 TNBC 的治疗效果。从机制上讲，CDK5 会切换 PPAR γ的 E3 泛素连接酶活性，并直接保护 ESRP1 免受泛素依赖性蛋白水解作用。这一发现首先表明，在 TNBC 治疗中，CDK5 阻断可以成为减少干细胞转化并增加对 PD-1 阻断的反应的有效策略。

更新日期：2020-11-19

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