The combination of vemurafenib and procaspase-3 activation is synergistic in mutant BRAF melanomas

Jessie Peh, Timothy M. Fan, Kathryn L. Wycislo, Howard S. Roth, Paul J. Hergenrother

Research output: Contribution to journalArticle

Abstract

The development of vemurafenib resistance limits the longterm efficacy of this drug for treatment of metastatic melanomas with theV600E BRAF mutation. Inhibition of downstream MAPK signaling with vemurafenib induces apoptotic cell death mediated by caspase-3, suggesting that addition of a procaspase-3 activator could enhance anticancer effects. Here, we show that the combination of PAC-1, a procaspase-activating compound, and vemurafenib is highly synergistic in enhancing caspase-3 activity and apoptotic cell death in melanoma cell lines harboring theV600E BRAF mutation. In vivo, the combination displays a favorable safety profile in mice and exerts significant antitumor effects. We further demonstrate that addition of PAC-1 to the clinically useful combination of vemurafenib and a MEK inhibitor, trametinib, starkly enhances the caspase-3 activity and proapoptotic effect of the combination. Moreover, addition of low concentration PAC-1 also delays the regrowth of cells following treatment with vemurafenib. Finally, PAC-1 remains potent against vemurafenib-resistant A375VR cells in cell culture and synergizes with vemurafenib to exert antitumor effects on A375VR cell growth in vivo. Collectively, our data suggest that inhibition of MAPK signaling combined with concurrent procaspase-3 activation is an effective strategy to enhance the antitumor activity of vemurafenib and mitigate the development of resistance.

Original languageEnglish (US)
Pages (from-to)1859-1869
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number8
DOIs
StatePublished - Aug 2016

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Caspase 3
Melanoma
Cell Death
Caspase 1
Mutation
PLX4032
Mitogen-Activated Protein Kinase Kinases
Cell Culture Techniques
Safety
Cell Line
2-carboxyarabinitol 1-phosphate
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The combination of vemurafenib and procaspase-3 activation is synergistic in mutant BRAF melanomas. / Peh, Jessie; Fan, Timothy M.; Wycislo, Kathryn L.; Roth, Howard S.; Hergenrother, Paul J.

In: Molecular Cancer Therapeutics, Vol. 15, No. 8, 08.2016, p. 1859-1869.

Research output: Contribution to journalArticle

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