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

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 journal › Article › peer-review

4 Scopus citations

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 language	English (US)
Pages (from-to)	8001-8012
Number of pages	12
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	14
DOIs	https://doi.org/10.1073/pnas.1912617117
State	Published - Apr 7 2020
Externally published	Yes

Keywords

CDK5
Cyclin-dependent kinases
Metastasis
Mouse cancer models

ASJC Scopus subject areas

General

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10.1073/pnas.1912617117

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Sharma, S., Zhang, T., Michowski, W., Rebecca, V. W., Xiao, M., Ferretti, R., Suski, J. M., Bronson, R. T., Paulo, J. A., Frederick, D., Fassl, A., Boland, G. M., Geng, Y., Lees, J. A., Medema, R. H., Herlyn, M., Gygi, S. P., & Sicinski, P. (2020). Targeting the cyclin-dependent kinase 5 in metastatic melanoma. Proceedings of the National Academy of Sciences of the United States of America, 117(14), 8001-8012. https://doi.org/10.1073/pnas.1912617117

Sharma, S, Zhang, T, Michowski, W, Rebecca, VW, Xiao, M, Ferretti, R, Suski, JM, Bronson, RT, Paulo, JA, Frederick, D, Fassl, A, Boland, GM, Geng, Y, Lees, JA, Medema, RH, Herlyn, M, Gygi, SP & Sicinski, P 2020, 'Targeting the cyclin-dependent kinase 5 in metastatic melanoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 14, pp. 8001-8012. https://doi.org/10.1073/pnas.1912617117

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title = "Targeting the cyclin-dependent kinase 5 in metastatic melanoma",

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.",

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

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doi = "10.1073/pnas.1912617117",

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AU - Ferretti, Roberta

AU - Suski, Jan M.

AU - Bronson, Roderick T.

AU - Paulo, Joao A.

AU - Frederick, Dennie

AU - Fassl, Anne

AU - Boland, Genevieve M.

AU - Geng, Yan

AU - Lees, Jacqueline A.

AU - Medema, Rene H.

AU - Herlyn, Meenhard

AU - Gygi, Steven P.

AU - Sicinski, Piotr

PY - 2020/4/7

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AB - 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.

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Targeting the cyclin-dependent kinase 5 in metastatic melanoma

Abstract

Keywords

ASJC Scopus subject areas

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