CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells

PLoS One. 2022 Sep 9;17(9):e0273711. doi: 10.1371/journal.pone.0273711. eCollection 2022.

Abstract

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18-2.6 μM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms* / drug therapy
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Melanoma* / pathology
  • Mutation
  • Neoplasm Recurrence, Local
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / metabolism
  • Pyrazines

Substances

  • 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(3-oxo-3,4-dihydropyrido(3,2-b)pyrazin-8-yloxy)phenyl)urea
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyrazines
  • Proto-Oncogene Proteins B-raf

Grants and funding

F.T. has been supported by The Norwegian Cancer Society (grant no 182716)(https://kreftforeningen.no/en/) and The Western Norway Regional Health Authority (grant no F-11970)(https://helse-vest.no/en/research-and-co-operation). A.R. and C.F.H. has been supported by The Medical Student Research Programme at The Faculty of Medicine, University of Bergen (https://www.uib.no/en/med/71062/medical-student-research-programme-faculty-medicine). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.