CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy

Yuncheng Bei; Nan Cheng; Ting Chen; Yuxin Shu; Ye Yang; Nanfei Yang; Xinyu Zhou; Baorui Liu; Jia Wei; Qin Liu; Wei Zheng; Wenlong Zhang; Huifang Su; Wei-Guo Zhu; Jianguo Ji; Pingping Shen

doi:10.1002/advs.202001417

CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy

Adv Sci (Weinh). 2020 Oct 15;7(22):2001417. doi: 10.1002/advs.202001417. eCollection 2020 Nov.

Authors

Yuncheng Bei¹, Nan Cheng¹, Ting Chen^{1

2}, Yuxin Shu¹, Ye Yang³, Nanfei Yang¹, Xinyu Zhou⁴, Baorui Liu⁵, Jia Wei⁵, Qin Liu⁵, Wei Zheng¹, Wenlong Zhang¹, Huifang Su¹, Wei-Guo Zhu⁶, Jianguo Ji⁴, Pingping Shen^{1

6}

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer Center Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing University Nanjing 210046 P. R. China.
² Laura and Isaac Perlmutter Cancer Center New York University Langone Medical Center New York NY USA.
³ State Key Laboratory Cultivation Base for TCM Quality and Efficacy Nanjing University of Chinese Medicine Nanjing 210023 P. R. China.
⁴ State Key Laboratory of Protein and Plant Gene Research College of Life Sciences Peking University Beijing 100871 P. R. China.
⁵ The Comprehensive Cancer Center Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 P. R. China.
⁶ Guangdong Key Laboratory of Genome Instability and Human Disease Shenzhen University Carson Cancer Center Department of Biochemistry and Molecular Biology Shenzhen University School of Medicine Shenzhen 518060 P. R. China.

Abstract

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.

Keywords: CD44 variants; CDK5; PPARγ phosphorylation; cancer stem cells; immune checkpoint blockade; triple‐negative breast cancer; tumor microenvironment.