The Combination of Vemurafenib and Procaspase-3 Activation Is Synergistic in Mutant BRAF Melanomas.

Autor:	Peh J; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois., Fan TM; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois. Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois., Wycislo KL; Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois., Roth HS; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois., Hergenrother PJ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois. hergenro@uiuc.edu.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2016 Aug; Vol. 15 (8), pp. 1859-69. Date of Electronic Publication: 2016 Jun 13.
DOI:	10.1158/1535-7163.MCT-16-0025
Abstrakt:	The development of vemurafenib resistance limits the long-term efficacy of this drug for treatment of metastatic melanomas with the (V600E)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 the (V600E)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. Mol Cancer Ther; 15(8); 1859-69. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu