Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy
Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy
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DOI：
10.1038/onc.2013.487
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发表时间：
2014-11-20
期刊：
影响因子：
8
通讯作者：
Robert, B.
中科院分区：
文献类型：
--
作者：
Leconet, W.;Larbouret, C.;Robert, B.
AXL受体酪氨酸激酶（RTK）与许多癌症的增殖和侵袭有关，特别是在胰腺导管腺癌（PDAC）中，迫切需要新的治疗选择。我们研究了特异性单克隆抗体（mAb）抑制AXL活性是否能有效限制胰腺癌细胞的增殖和迁移。采用免疫组化法检测42例PDAC中AXL的表达。在胰腺癌细胞系中使用短发夹RNA方法研究了AXL在肿瘤发生中的作用。我们进一步产生了抗人AXL单克隆抗体，并首先在体外，在一组胰腺癌细胞系中，然后在体内，使用皮下或原位胰腺肿瘤异种移植物，评估其抑制作用和AXL下游信号通路。AXL受体在76%（32/ 42）的PDAC中表达，主要存在于侵袭性细胞中。AXL敲低的Panc-1细胞减少了体外细胞迁移、存活和增殖，并减少了体内肿瘤生长。两种选定的抗AXL mAb（D9和E8）可抑制AXL及其下游靶点AKT的磷酸化，而不影响生长停滞特异性因子6（GAS 6）结合，通过内化诱导AXL的下调表达，从而抑制增殖和迁移研究的四种胰腺癌细胞系。在体内，抗AXL mAb治疗显著降低了皮下和原位胰腺肿瘤异种移植物的生长，与其KRAS突变状态无关。我们的体外和临床前体内数据表明，抗人AXL mAb可能代表胰腺癌免疫治疗的新方法。
AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/ 42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy.