title: Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5.
abstract: Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome-associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas.
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: María
authors.initials: M
authors.lastname: García-Fernández
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karras
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Checinska
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Cañón
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Guadalupe T
authors.initials: GT
authors.lastname: Calvo
authors.affiliation: b Bioinformatics Unit , Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Metehan
authors.initials: M
authors.lastname: Cifdaloz
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Colmenar
authors.affiliation: c Cytogenetics Unit , Spanish National Cancer Research Center (CNIO) , Madrid , Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Espinosa-Hevia
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: David
authors.initials: D
authors.lastname: Olmeda
authors.affiliation: a Melanoma Laboratory , Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO) , Madrid , Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Soengas
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000235:genetics*; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006579:Heterozygote; D019656:Loss of Heterozygosity / Q000235:genetics*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D009506:Nevus / Q000235:genetics / Q000473:pathology; D010858:Pigmentation / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D048493:Proto-Oncogene Proteins B-raf
keywords: ATG5; copy number variation; core autophagy genes; lineage-specificity; melanoma; mouse models; patient prognosis; targeted therapy