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Oncogenic B-RAF Signaling in Melanoma Impairs the Therapeutic Advantage of Autophagy Inhibition

Lookup NU author(s): Dr Jane Renwick, Shaun Martin, Dr David Hill, Nicola Townshend, Dr Chris RedfernORCiD, Professor Penny Lovat

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Abstract

Purpose: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy. Experimental Design: Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model. Results: Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild-type cells, shown by increased conversion of LC3 to the autophagic vesicle-associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF-mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide-or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF-mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function. Conclusions: Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma. Clin Cancer Res; 17(8); 2216-26. (C) 2011 AACR.

Publication metadata

Author(s): Armstrong JL, Corazzari M, Martin S, Pagliarini V, Falasca L, Hill DS, Ellis N, Al Sabah S, Redfern CPF, Fimia GM, Piacentini M, Lovat PE

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2011

Volume: 17

Issue: 8

Pages: 2216-2226

Print publication date: 15/04/2011

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-10-3003

DOI: 10.1158/1078-0432.CCR-10-3003

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