Targeting the cyclin-dependent kinase 5 in metastatic melanoma

Samanta Sharma, Tian Zhang, Wojciech Michowski, Vito W. Rebecca, Min Xiao, Roberta Ferretti, Jan M. Suski, Roderick T. Bronson, Joao A. Paulo, Dennie Frederick, Anne Fassl, Genevieve M. Boland, Yan Geng, Jacqueline A. Lees, Rene H. Medema, Meenhard Herlyn, Steven P. Gygi, Piotr Sicinski

Research output: Contribution to journalArticlepeer-review

Abstract

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.

Original languageEnglish (US)
Pages (from-to)8001-8012
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number14
DOIs
StatePublished - Apr 7 2020
Externally publishedYes

Keywords

  • CDK5
  • Cyclin-dependent kinases
  • Metastasis
  • Mouse cancer models

ASJC Scopus subject areas

  • General

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