Vemurafenib Synergizes with Nutlin-3 to Deplete Survivin and Suppresses Melanoma Viability and Tumor Growth
(2013) In Clinical Cancer Research 19(16). p.4383-4391- 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... (More)
- 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. (C)2013 AACR. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4025860
- author
- Ji, Zhenyu ; Kumar, Raj ; Taylor, Michael ; Rajadurai, Anpuchchelvi ; Marzuka-Alcala, Alexander ; Chen, Y. Erin ; Njauw, Ching-Ni Jenny ; Flaherty, Keith ; Jönsson, Göran B LU and Tsao, Hensin
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Clinical Cancer Research
- volume
- 19
- issue
- 16
- pages
- 4383 - 4391
- publisher
- American Association for Cancer Research
- external identifiers
-
- wos:000323147700011
- scopus:84882992810
- pmid:23812671
- ISSN
- 1078-0432
- DOI
- 10.1158/1078-0432.CCR-13-0074
- language
- English
- LU publication?
- yes
- id
- 4afbcf43-1689-4376-b60f-2967e5a0ee21 (old id 4025860)
- date added to LUP
- 2016-04-01 09:52:27
- date last changed
- 2022-04-27 08:24:20
@article{4afbcf43-1689-4376-b60f-2967e5a0ee21,
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. (C)2013 AACR.}},
author = {{Ji, Zhenyu and Kumar, Raj and Taylor, Michael and Rajadurai, Anpuchchelvi and Marzuka-Alcala, Alexander and Chen, Y. Erin and Njauw, Ching-Ni Jenny and Flaherty, Keith and Jönsson, Göran B and Tsao, Hensin}},
issn = {{1078-0432}},
language = {{eng}},
number = {{16}},
pages = {{4383--4391}},
publisher = {{American Association for Cancer Research}},
series = {{Clinical Cancer Research}},
title = {{Vemurafenib Synergizes with Nutlin-3 to Deplete Survivin and Suppresses Melanoma Viability and Tumor Growth}},
url = {{http://dx.doi.org/10.1158/1078-0432.CCR-13-0074}},
doi = {{10.1158/1078-0432.CCR-13-0074}},
volume = {{19}},
year = {{2013}},
}