VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers.
VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers.
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DOI：
10.1111/cas.14801
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发表时间：
2021-05
期刊：
影响因子：
5.7
通讯作者：
Kiura K
中科院分区：
文献类型：
--
作者：
Watanabe H;Ichihara E;Kayatani H;Makimoto G;Ninomiya K;Nishii K;Higo H;Ando C;Okawa S;Nakasuka T;Kano H;Hara N;Hirabae A;Kato Y;Ninomiya T;Kubo T;Rai K;Ohashi K;Hotta K;Tabata M;Maeda Y;Kiura K
靶向表皮生长因子受体（EGFR）、间变性淋巴瘤激酶（ALK）或c-ros癌基因1（ROS 1）改变的分子药物彻底改变了癌基因驱动的非小细胞肺癌（NSCLC）的治疗。然而，获得性耐药性的出现仍然是一个重大挑战，限制了这些分子靶向治疗的更广泛的临床成功。在这项研究中，我们研究了各种分子靶向药物（包括厄洛替尼、阿来替尼和克唑替尼）联合抗血管内皮生长因子受体（VEGFR）2治疗的疗效。VEGFR 2阻断剂与分子靶向药物联合使用增强了这些药物在EGFR-、ALK-或ROS 1改变的NSCLC异种移植小鼠模型中的抗肿瘤作用。与单独使用分子靶向药物治疗的小鼠相比，使用抗VEGFR 2抗体与分子靶向药物联合治疗的小鼠肿瘤中的CD 31阳性血管数量显著降低，这表明VEGFR 2阻断具有抗血管生成作用。此外，联合治疗在EGFR-、ALK-或ROS 1-改变的NSCLC细胞中发挥了更有效的体外抗增殖作用，这意味着VEGFR 2抑制对癌细胞也具有直接的抗肿瘤作用。此外，暴露于分子靶向药物后诱导VEGFR 2表达，这意味着VEGFR 2信号传导在接受分子靶向治疗的NSCLC患者中的重要性。总之，VEGFR 2抑制增强了分子靶向药物在各种癌基因驱动的NSCLC模型中的抗肿瘤作用，不仅通过抑制肿瘤血管生成，还通过对癌细胞施加直接的抗增殖作用。因此，抗VEGFR 2抗体和分子靶向药物的联合治疗可作为癌基因驱动的NSCLC的有前景的治疗策略。我们发现，VEGFR 2阻断增强了分子靶向药物在癌基因驱动的NSCLC中的抗肿瘤作用，特别是在EGFR/ALK/ROS 1驱动的NSCLC中。我们还确定了抗VEGFR 2治疗与分子靶向药物协同作用的2种机制。VEGFR 2阻断不仅抑制肿瘤血管生成，而且对癌细胞产生直接的抗增殖作用。
Molecular agents targeting the epidermal growth factor receptor (EGFR)‐, anaplastic lymphoma kinase (ALK)‐ or c‐ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene‐driven non‐small‐cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti‐vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti‐tumor effects of these agents in xenograft mouse models of EGFR‐, ALK‐, or ROS1‐altered NSCLC. The numbers of CD31‐positive blood vessels were significantly lower in the tumors of mice treated with an anti‐VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR‐, ALK‐, or ROS1‐altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti‐tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti‐tumor effects of molecular targeted agents in various oncogene‐driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti‐VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene‐driven NSCLC. We found that VEGFR2 blockade augmented the anti‐tumor effects of molecular targeted agents in oncogene‐driven NSCLC, particularly in EGFR/ALK/ROS1‐driven NSCLC. We also identified 2 mechanisms underlying the synergistic effects of anti‐VEGFR2 therapy with molecular targeted agents. VEGFR2 blockade not only inhibited tumor angiogenesis but also exerted direct antiproliferative effects on cancer cells.
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影响因子：
5.7
作者：
Kato Y;Ninomiya K;Ohashi K;Tomida S;Makimoto G;Watanabe H;Kudo K;Matsumoto S;Umemura S;Goto K;Ichihara E;Ninomiya T;Kubo T;Sato A;Hotta K;Tabata M;Toyooka S;Maeda Y;Kiura K
通讯作者：
Kiura K
影响因子：
5.7
作者：
Watanabe H;Ichihara E;Kayatani H;Makimoto G;Ninomiya K;Nishii K;Higo H;Ando C;Okawa S;Nakasuka T;Kano H;Hara N;Hirabae A;Kato Y;Ninomiya T;Kubo T;Rai K;Ohashi K;Hotta K;Tabata M;Maeda Y;Kiura K
通讯作者：
Kiura K
影响因子：
20.4
作者：
Ichihara, Eiki;Hotta, Katsuyuki;Kiura, Katsuyuki
通讯作者：
Kiura, Katsuyuki
影响因子：
158.5
作者：
Sandler, Alan;Gray, Robert;Johnson, David H.
通讯作者：
Johnson, David H.
影响因子：
158.5
作者：
Solomon, Benjamin J.;Mok, Tony;Waqar, S.
通讯作者：
Waqar, S.