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

doi:10.1073/pnas.1912617117

Targeting the cyclin-dependent kinase 5 in metastatic melanoma

Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):8001-8012. doi: 10.1073/pnas.1912617117. Epub 2020 Mar 19.

Authors

Samanta Sharma^{1

2}, Tian Zhang³, Wojciech Michowski^{1

2}, Vito W Rebecca⁴, Min Xiao⁴, Roberta Ferretti^{5

6}, Jan M Suski^{1

2}, Roderick T Bronson⁷, Joao A Paulo³, Dennie Frederick⁸, Anne Fassl^{1

2}, Genevieve M Boland⁸, Yan Geng^{1

2}, Jacqueline A Lees^{5

9}, Rene H Medema¹⁰, Meenhard Herlyn⁴, Steven P Gygi³, Piotr Sicinski^{11

2}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line, Tumor
Cell Movement / drug effects
Cell Movement / genetics
Cyclin-Dependent Kinase 5 / antagonists & inhibitors
Cyclin-Dependent Kinase 5 / genetics
Cyclin-Dependent Kinase 5 / metabolism*
Female
Gene Dosage
Humans
Male
Melanoma / drug therapy
Melanoma / genetics
Melanoma / mortality
Melanoma / pathology*
Melanoma, Experimental / drug therapy
Melanoma, Experimental / genetics
Melanoma, Experimental / pathology*
Mice
Mice, Knockout
Phosphorylation / drug effects
Phosphorylation / genetics
Prognosis
Skin / pathology
Skin Neoplasms / drug therapy
Skin Neoplasms / genetics
Skin Neoplasms / mortality
Skin Neoplasms / pathology*
Vimentin / metabolism
Xenograft Model Antitumor Assays

Substances

VIM protein, human
Vim protein, mouse
Vimentin
Cyclin-Dependent Kinase 5
CDK5 protein, human
Cdk5 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding