Open AccessDabrafenib inhibits the growth of BRAF‐WT cancers through CDK16 and NEK9 inhibition
Author(s) -
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.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12152
Subject(s) - dabrafenib , cancer research , growth inhibition , microbiology and biotechnology , cell growth , biology , chemistry , medicine , genetics , melanoma , vemurafenib , metastatic melanoma
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.