Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth
Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth
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DOI：
10.1073/pnas.1222893110
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发表时间：
2013-02-26
影响因子：
11.1
通讯作者：
van de Rijn, Matt
中科院分区：
文献类型：
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作者：
Edris, Badreddin;Willingham, Stephen B.;van de Rijn, Matt
胃肠道间质瘤(GIST)是胃肠道最常见的肉瘤，起源于Cajal间质细胞。其特征是表达受体酪氨酸激酶CD117(KIT)。在70-80%的GIST病例中，KIT中存在致癌基因突变，导致受体的结构性激活，从而推动这些肿瘤的增殖。使用小分子酪氨酸激酶抑制剂伊马替尼治疗GIST会抑制KIT介导的信号转导，最初在KIT阳性的GIST患者中有70%-85%的患者得到了疾病控制。然而，绝大多数患者最终对伊马替尼治疗产生抗药性，导致疾病进展，并对这些肿瘤的临床管理构成重大挑战。在这里，我们展示了一种抗KIT单抗(MAb)，SR1，能够在体外减缓三种人GIST细胞系的生长。重要的是，在对伊马替尼耐药和对伊马替尼敏感的GIST细胞系中，这些细胞生长的减少是相同的。SR1处理GIST细胞系可减少细胞表面KIT的表达，提示mAb诱导KIT下调可能是SR1抑制GIST生长的机制之一。此外，我们还表明，SR1治疗增强了巨噬细胞对GIST细胞的吞噬作用，表明SR1治疗可能增强免疫细胞介导的肿瘤清除。最后，使用两种对伊马替尼敏感和耐药的GIST异种移植模型，我们证明了SR1能够在体内强烈地抑制肿瘤的生长。这些结果表明，用单抗靶向试剂盒治疗GIST可能是一种替代或补充的方法。
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract and arises from the interstitial cells of Cajal. It is characterized by expression of the receptor tyrosine kinase CD117 (KIT). In 70-80% of GIST cases, oncogenic mutations in KIT are present, leading to constitutive activation of the receptor, which drives the proliferation of these tumors. Treatment of GIST with imatinib, a small-molecule tyrosine kinase inhibitor, inhibits KIT-mediated signaling and initially results in disease control in 70-85% of patients with KIT-positive GIST. However, the vast majority of patients eventually develop resistance to imatinib treatment, leading to disease progression and posing a significant challenge in the clinical management of these tumors. Here, we show that an anti-KIT monoclonal antibody (mAb), SR1, is able to slow the growth of three human GIST cell lines in vitro. Importantly, these reductions in cell growth were equivalent between imatinib-resistant and imatinib-sensitive GIST cell lines. Treatment of GIST cell lines with SR1 reduces cell-surface KIT expression, suggesting that mAb-induced KIT down-regulation may be a mechanism by which SR1 inhibits GIST growth. Furthermore, we also show that SR1 treatment enhances phagocytosis of GIST cells by macrophages, indicating that treatment with SR1 may enhance immune cell-mediated tumor clearance. Finally, using two xenotransplantation models of imatinib-sensitive and imatinib-resistant GIST, we demonstrate that SR1 is able to strongly inhibit tumor growth in vivo. These results suggest that treatment with mAbs targeting KIT may represent an alternative, or complementary, approach for treating GIST.