MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB.
MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB.
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DOI：
10.1158/1078-0432.ccr-16-1192
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发表时间：
2016-12-15
期刊：
影响因子：
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通讯作者：
Siegel PM
中科院分区：
文献类型：
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作者：
Rose AA;Annis MG;Frederick DT;Biondini M;Dong Z;Kwong L;Chin L;Keler T;Hawthorne T;Watson IR;Flaherty KT;Siegel PM
确定BRAF和/或MEK受体诱导的GPNMB表达是否使黑色素瘤对靶向GPNMB的抗体-药物缀合物CDX-011敏感。询问TCGA黑色素瘤数据集的一组MITF调节的黑色素体分化抗原，包括GPNMB。通过RT-qPCR、免疫印迹和FACs分析评估用BRAF或MEK抑制剂处理的BRAF突变黑素瘤细胞系的GPNMB表达。使用瞬时siRNA介导的敲低方法来确定MITF是否是治疗诱导的GPNMB上调所需的。在MAPK抑制剂治疗的疾病进展之前、期间和之后，在来自黑素瘤患者的连续活检和血清样品中分析GPNMB表达。进行皮下注射以测试单独的MAPK抑制剂、单独的CDX-011或它们的组合在抑制黑素瘤生长中的功效。MITF依赖的黑素体分化标记与该疾病患者的不良预后相关。MITF在BRAF和MEK抑制剂处理后增加，并诱导黑素体分化基因（包括GPNMB）的表达。GPNMB在MAPK通路抑制剂处理的黑色素瘤细胞的细胞表面表达，并且在接受MAPK通路抑制剂的黑色素瘤患者的治疗中与治疗前活检中也升高。将BRAF和/或MEK抑制剂与CDX-011（一种靶向GPNMB的抗体-药物-缀合物）组合在临床前动物模型中有效引起黑素瘤消退，并延迟单独用MEK或BRAF/MEK抑制剂治疗观察到的复发性黑素瘤生长。MAPK通路抑制剂与靶向GPNMB的抗体-药物-缀合物的组合是黑素瘤患者的有效治疗选择。
To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. The TCGA melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot and FACs analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pre-treatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug-conjugate targeting GPNMB, is effective in causing melanoma regression in pre-clinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. The combination of MAPK pathway inhibitors with an antibody-drug-conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma.