Division of Cancer Medicine and Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2017 Sep 15;23(18):5489-5501. doi: 10.1158/1078-0432.CCR-16-3216. Epub 2017 May 30.
Resistance to VEGFR inhibitors is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). We investigated the cellular mechanisms mediating resistance of NSCLCs to VEGFR tyrosine kinase inhibitors. We generated murine models of human NSCLC and performed targeted inhibition studies with the VEGFR TKIs cediranib and vandetanib. We used species-specific hybridization of microarrays to compare cancer (human) and stromal (mouse) cell transcriptomes of TKI-sensitive and -resistant tumors. We measured tumor microvascular density and vessel tortuosity to characterize the effects of therapy on the tumor vascular bed. Circulating cytokine and angiogenic factor levels in patients enrolled in VEGFR TKI trials were correlated with clinical outcomes. Murine xenograft models of human lung adenocarcinoma were initially sensitive to VEGFR TKIs, but developed resistance to treatment. Species-specific microarray analysis identified increased expression of stromal-derived hepatocyte growth factor (HGF) as a candidate mediator of TKI resistance and its receptor, c-MET, was activated in cancer cells and tumor-associated stroma. A transient increase in hypoxia-regulated molecules in the initial response phase was followed by adaptive changes resulting in a more tortuous vasculature. Forced HGF expression in cancer cells reduced tumor sensitivity to VEGFR TKIs and produced tumors with tortuous blood vessels. Dual VEGFR/c-MET signaling inhibition delayed the onset of the resistant phenotype and prevented the vascular morphology alterations. In patients with cancer receiving VEGFR TKIs, high pretreatment HGF plasma levels correlated with poorer survival. HGF/c-MET pathway mediates VEGFR inhibitor resistance and vascular remodeling in NSCLC. .
血管内皮生长因子受体（VEGFR）抑制剂耐药是治疗非小细胞肺癌（NSCLC）的主要障碍。我们研究了介导 NSCLC 对 VEGFR 酪氨酸激酶抑制剂耐药的细胞机制。我们构建了人 NSCLC 的小鼠模型，并对 VEGFR TKIs 西地尼布和凡德他尼进行了靶向抑制研究。我们使用种间杂交微阵列比较了 TKI 敏感和耐药肿瘤的癌细胞（人）和基质细胞（鼠）转录组。我们测量了肿瘤微血管密度和血管迂曲度，以表征治疗对肿瘤血管床的影响。我们还分析了参加 VEGFR TKI 试验的患者的循环细胞因子和血管生成因子水平，并与临床结果相关联。人肺腺癌的小鼠异种移植模型最初对 VEGFR TKIs 敏感，但对治疗产生耐药性。种间微阵列分析鉴定出基质衍生的肝细胞生长因子（HGF）表达增加是 TKI 耐药的候选介质，其受体 c-MET 在癌细胞和肿瘤相关基质中被激活。在初始反应阶段，缺氧调节分子短暂增加，随后适应性改变导致血管更加迂曲。在癌细胞中强制表达 HGF 会降低肿瘤对 VEGFR TKIs 的敏感性，并产生血管迂曲的肿瘤。双重 VEGFR/c-MET 信号抑制延迟了耐药表型的发生，并防止了血管形态改变。在接受 VEGFR TKIs 治疗的癌症患者中，高预处理 HGF 血浆水平与较差的生存相关。HGF/c-MET 通路介导 NSCLC 中 VEGFR 抑制剂耐药和血管重塑。
