Cargando…
Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF‐mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS‐mutant and KRAS‐mutant cancer cell lines than...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748485/ https://www.ncbi.nlm.nih.gov/pubmed/29112787 http://dx.doi.org/10.1002/1878-0261.12152 |
_version_ | 1783289408003244032 |
---|---|
author | Phadke, Manali Remsing Rix, Lily L. Smalley, Inna Bryant, Annamarie T. Luo, Yunting Lawrence, Harshani R. Schaible, Braydon J. Chen, Yian A. Rix, Uwe Smalley, Keiran S. M. |
author_facet | Phadke, Manali Remsing Rix, Lily L. Smalley, Inna Bryant, Annamarie T. Luo, Yunting Lawrence, Harshani R. Schaible, Braydon J. Chen, Yian A. Rix, Uwe Smalley, Keiran S. M. |
author_sort | Phadke, Manali |
collection | PubMed |
description | Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF‐mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS‐mutant and KRAS‐mutant cancer cell lines than vemurafenib. Using mass spectrometry‐based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS‐ and KRAS‐mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho‐CHK1, decreased CDK4 expression, and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS‐ and KRAS‐mutant cancer cells by dabrafenib, but not vemurafenib. Combined silencing of NEK9 and CDK16 was associated with enhanced inhibition of melanoma cell proliferation. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. |
format | Online Article Text |
id | pubmed-5748485 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57484852018-01-04 Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition Phadke, Manali Remsing Rix, Lily L. Smalley, Inna Bryant, Annamarie T. Luo, Yunting Lawrence, Harshani R. Schaible, Braydon J. Chen, Yian A. Rix, Uwe Smalley, Keiran S. M. Mol Oncol Research Articles Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF‐mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS‐mutant and KRAS‐mutant cancer cell lines than vemurafenib. Using mass spectrometry‐based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS‐ and KRAS‐mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho‐CHK1, decreased CDK4 expression, and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS‐ and KRAS‐mutant cancer cells by dabrafenib, but not vemurafenib. Combined silencing of NEK9 and CDK16 was associated with enhanced inhibition of melanoma cell proliferation. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. John Wiley and Sons Inc. 2017-11-23 2018-01 /pmc/articles/PMC5748485/ /pubmed/29112787 http://dx.doi.org/10.1002/1878-0261.12152 Text en © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Phadke, Manali Remsing Rix, Lily L. Smalley, Inna Bryant, Annamarie T. Luo, Yunting Lawrence, Harshani R. Schaible, Braydon J. Chen, Yian A. Rix, Uwe Smalley, Keiran S. M. Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition |
title | Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition |
title_full | Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition |
title_fullStr | Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition |
title_full_unstemmed | Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition |
title_short | Dabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition |
title_sort | dabrafenib inhibits the growth of braf‐wt cancers through cdk16 and nek9 inhibition |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748485/ https://www.ncbi.nlm.nih.gov/pubmed/29112787 http://dx.doi.org/10.1002/1878-0261.12152 |
work_keys_str_mv | AT phadkemanali dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT remsingrixlilyl dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT smalleyinna dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT bryantannamariet dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT luoyunting dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT lawrenceharshanir dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT schaiblebraydonj dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT chenyiana dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT rixuwe dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition AT smalleykeiransm dabrafenibinhibitsthegrowthofbrafwtcancersthroughcdk16andnek9inhibition |