Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4321-6. doi: 10.1073/pnas.1205575110. Epub 2013 Feb 27.
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.
尽管针对丝氨酸/苏氨酸激酶 BRAF 的致癌突变的小分子抑制剂可导致黑色素瘤患者的显著临床反应，但几乎所有患者的肿瘤都无法被根除。通过鉴定保护肿瘤细胞免于死亡的内在机制，将有助于成功的治疗。在这里，我们使用生物信息学方法来鉴定可靶向治疗的、仅限于肿瘤与正常组织的“驱动”致癌基因。将该方法应用于 88 种短期黑色素瘤细胞培养物，我们发现抗凋亡 BCL2 家族成员 BCL2A1 在约 30%的黑色素瘤中反复扩增，是黑色素瘤生长所必需的。BCL2A1 的过表达也促进了 BRAF 永生化黑素细胞的致瘤性。我们发现，由于黑色素瘤致癌基因 MITF 的直接转录控制，BCL2A1 的高表达仅限于黑色素瘤。尽管 BRAF 抑制剂可导致细胞周期停滞和适度凋亡，但我们发现，在 BCL2A1 或 MITF 扩增的黑色素瘤中，抑制 BCL2A1 可显著增强凋亡。此外，我们发现 BCL2A1 的表达与黑色素瘤患者对 BRAF 通路抑制剂的临床反应较差相关。BRAF 抑制剂与 obatoclax（一种 BCL2A1 和其他 BCL2 家族成员的抑制剂）联合治疗黑色素瘤，可克服 BCL2A1 扩增细胞体外和体内对 BRAF 抑制剂的内在耐药性。这些研究确定 MITF-BCL2A1 为黑色素瘤中的谱系特异性致癌途径，并强调了其对改善 BRAF 靶向治疗反应的作用。
