Reference Detail

Ref Type

Journal Article

PMID

(27297867)

Authors

Peh J, Fan TM, Wycislo KL, Roth HS, Hergenrother PJ

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	8	2016 Aug	1859-69	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PAC-1	PAC-1	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PAC-1		VO-100		PAC-1 is a small molecule activator of procaspase 3, which occurs via inhibition of zinc ions, resulting in autoactivation and thus, may lead to apoptotis and anti-tumor activity (PMID: 19281821, PMID: 27297867).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	PAC-1 + Trametinib + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of PAC-1 to Mekinist (trametinib) and Zelboraf (vemurafenib) led to greater levels of caspase-3 activity and apoptosis in melanoma cells harboring BRAF V600E when compared to Zelboraf (vemurafenib) and Mekinist (trametinib) treatment without PAC-1 (PMID: 27297867).	27297867
BRAF V600E	melanoma	sensitive	PAC-1 + Vemurafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of PAC-1 and Zelboraf (vemurafenib) resulted in a synergistic effect when treating melanoma cells harboring BRAF V600E in culture and xenograft models, demonstrating increased apoptosis and decreased tumor volume (PMID: 27297867).	27297867