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Proc Natl Acad Sci U S A. 2020 Mar 19. pii: 201912617. doi: 10.1073/pnas.1912617117. [Epub ahead of print]

Targeting the cyclin-dependent kinase 5 in metastatic melanoma.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
2
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
3
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
4
Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104.
5
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
6
Translational Innovation Platform Oncology, Emmanuel Merck Darmstadt (EMD) Serono Research and Development Institute, Inc., Billerica, MA 01821.
7
Rodent Histopathology Core, Harvard Medical School, Boston, MA 02115.
8
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
9
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
10
Division of Cell Biology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
11
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215; peter_sicinski@dfci.harvard.edu.

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.

KEYWORDS:

CDK5; cyclin-dependent kinases; metastasis; mouse cancer models

PMID:
32193336
DOI:
10.1073/pnas.1912617117

Conflict of interest statement

Competing interest statement: P.S. has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, and Exo Therapeutics; his laboratory receives research funding from Novartis. W.M. is currently an employee of Cedilla Therapeutics.

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