Wang Tao, Xiao Min, Ge Yingbin, Krepler Clemens, Belser Eric, Lopez-Coral Alfonso, Xu Xiaowei, Zhang Gao, Azuma Rikka, Liu Qin, Liu Rui, Li Ling, Amaravadi Ravi K, Xu Wei, Karakousis Giorgos, Gangadhar Tara C, Schuchter Lynn M, Lieu Melissa, Khare Sanika, Halloran Molly B, Herlyn Meenhard, Kaufman Russel E
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania.
Department of Physiology, Nanjing Medical University, Nanjing, China.
Clin Cancer Res. 2015 Apr 1;21(7):1652-64. doi: 10.1158/1078-0432.CCR-14-1554. Epub 2015 Jan 23.
To investigate the roles of melanoma-associated macrophages in melanoma resistance to BRAF inhibitors (BRAFi).
An in vitro macrophage and melanoma cell coculture system was used to investigate whether macrophages play a role in melanoma resistance to BRAFi. The effects of macrophages in tumor resistance were examined by proliferation assay, cell death assay, and Western blot analyses. Furthermore, two mouse preclinical models were used to validate whether targeting macrophages can increase the antitumor activity of BRAFi. Finally, the number of macrophages in melanoma tissues was examined by immunohistochemistry.
We demonstrate that in BRAF-mutant melanomas, BRAFi paradoxically activate the mitogen-activated protein kinase (MAPK) pathway in macrophages to produce VEGF, which reactivates the MAPK pathway and stimulates cell growth in melanoma cells. Blocking the MAPK pathway or VEGF signaling then reverses macrophage-mediated resistance. Targeting macrophages increases the antitumor activity of BRAFi in mouse and human tumor models. The presence of macrophages in melanomas predicts early relapse after therapy.
Our findings demonstrate that macrophages play a critical role in melanoma resistance to BRAFi, suggesting that targeting macrophages will benefit patients with BRAF-mutant melanoma.
研究黑色素瘤相关巨噬细胞在黑色素瘤对BRAF抑制剂（BRAFi）耐药中的作用。
采用体外巨噬细胞与黑色素瘤细胞共培养系统，研究巨噬细胞是否在黑色素瘤对BRAFi的耐药中发挥作用。通过增殖试验、细胞死亡试验和蛋白质免疫印迹分析检测巨噬细胞在肿瘤耐药中的作用。此外，使用两种小鼠临床前模型验证靶向巨噬细胞是否能增强BRAFi的抗肿瘤活性。最后，通过免疫组织化学检测黑色素瘤组织中的巨噬细胞数量。
我们证明，在BRAF突变的黑色素瘤中，BRAFi反常地激活巨噬细胞中的丝裂原活化蛋白激酶（MAPK）途径以产生VEGF，这会重新激活MAPK途径并刺激黑色素瘤细胞的生长。阻断MAPK途径或VEGF信号传导可逆转巨噬细胞介导的耐药性。在小鼠和人类肿瘤模型中，靶向巨噬细胞可增强BRAFi的抗肿瘤活性。黑色素瘤中巨噬细胞的存在预示着治疗后早期复发。
我们的研究结果表明，巨噬细胞在黑色素瘤对BRAFi的耐药中起关键作用，这表明靶向巨噬细胞将使BRAF突变的黑色素瘤患者受益。
