Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth.

Abstract

PURPOSE:

For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition.

EXPERIMENTAL DESIGN:

Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib.

RESULTS:

Dual targeting of BRAF(V600E) and Hdm2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3's effects fully and vemurafenib's effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the antiapoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy.

CONCLUSION:

These results show preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target.

• Authors: Zhenyu Ji, Raj Kumar, Michael Taylor, Anpuchchelvi Rajadurai, Alexander Marzuka-Alcalá, Y Erin Chen, Ching-Ni Jenny Njauw, Keith Flaherty, Göran Jönsson, Hensin Tsao
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 16 Pg. 4383-91 (Aug 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23812671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Imidazoles
• Indoles
• Inhibitor of Apoptosis Proteins
• Piperazines
• Sulfonamides
• Survivin
• Vemurafenib
• nutlin 3
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Melanoma (genetics, metabolism, pathology)
• Mice
• Models, Biological
• Mutation
• Piperazines (pharmacology)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Sulfonamides (pharmacology)
• Survivin
• Tumor Burden (drug effects)
• Vemurafenib