Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors.

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  • Additional Information
    • Source:
      Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
    • Publication Information:
      Publication: <2002->: Basingstoke : Nature Publishing Group
      Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
    • Subject Terms:
      Embryo, Nonmammalian/*cytology ; MAP Kinase Kinase 1/*antagonists & inhibitors ; Melanoma/*drug therapy ; Small Molecule Libraries/*pharmacology ; Zebrafish/*growth & development ; p21-Activated Kinases/*antagonists & inhibitors ; rac1 GTP-Binding Protein/*antagonists & inhibitors; Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Proliferation ; Embryo, Nonmammalian/drug effects ; Embryo, Nonmammalian/metabolism ; Female ; Humans ; MAP Kinase Kinase 1/genetics ; MAP Kinase Kinase 1/metabolism ; Male ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Nude ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Zebrafish/metabolism ; p21-Activated Kinases/genetics ; p21-Activated Kinases/metabolism ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism
    • Abstract:
      Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small-molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1. In this work, we explore the effects of PAK inhibition on RAC1 P29S signaling in zebrafish embryonic development, in the proliferation, survival and motility of RAC1 P29S -mutant human melanoma cells, and on tumor formation and progression from such cells in mice. We report that RAC1 P29S evokes a Rasopathy-like phenotype on zebrafish development that can be blocked by inhibitors of PAK or MEK. We also found and that RAC1-mutant human melanoma cells are resistant to clinical inhibitors of BRAF but are uniquely sensitive to PAK inhibitors. These data suggest that suppressing the PAK pathway might be of therapeutic benefit in this type of melanoma.
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    • Grant Information:
      P30 CA006927 United States CA NCI NIH HHS; R01 CA142928 United States CA NCI NIH HHS
    • Accession Number:
      0 (Biomarkers, Tumor)
      0 (RAC1 protein, human)
      0 (Small Molecule Libraries)
      EC 2.7.11.1 (PAK1 protein, human)
      EC 2.7.11.1 (p21-Activated Kinases)
      EC 2.7.12.2 (MAP Kinase Kinase 1)
      EC 2.7.12.2 (MAP2K1 protein, human)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
    • Publication Date:
      Date Created: 20171024 Date Completed: 20190306 Latest Revision: 20220409
    • Publication Date:
      20221213
    • Accession Number:
      PMC5814328
    • Accession Number:
      10.1038/onc.2017.400
    • Accession Number:
      29059171