title: BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition.
abstract: Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.
authors: Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
authors: Rizwan
authors: R
authors: Haq
authors: Satoru
authors: S
authors: Yokoyama
authors: Elena B
authors: EB
authors: Hawryluk
authors: Göran B
authors: GB
authors: Jönsson
authors: Dennie Tompers
authors: DT
authors: Frederick
authors: Kevin
authors: K
authors: McHenry
authors: Dale
authors: D
authors: Porter
authors: Thanh-Nga
authors: TN
authors: Tran
authors: Kevin T
authors: KT
authors: Love
authors: Robert
authors: R
authors: Langer
authors: Daniel G
authors: DG
authors: Anderson
authors: Levi A
authors: LA
authors: Garraway
authors: Lyn McDivitt
authors: LM
authors: Duncan
authors: Donald L
authors: DL
authors: Morton
authors: Dave S B
authors: DS
authors: Hoon
authors: Jennifer A
authors: JA
authors: Wargo
authors: Jun S
authors: JS
authors: Song
authors: David E
authors: DE
authors: Fisher
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019008:Drug Resistance, Neoplasm; D005784:Gene Amplification / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D051034:Inhibitor of Apoptosis Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf