Integration of pharmacoproteomic and computational approaches reveals the cellular signal transduction pathways affected by apatinib in gastric cancer cell lines
Integration of pharmacoproteomic and computational approaches reveals the cellular signal transduction pathways affected by apatinib in gastric cancer cell lines
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DOI：
10.1016/j.csbj.2023.03.006
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发表时间：
2023-03-24
影响因子：
6
通讯作者：
Adachi，Jun
中科院分区：
文献类型：
--
作者：
Nojima，Yosui;Aoki，Masahiko;Adachi，Jun
阿帕替尼是一种高选择性的血管内皮生长因子受体2（VEGFR 2）抑制剂，具有抗血管生成和抗肿瘤特性。在III期研究中，阿帕替尼的客观缓解率较低。目前尚不清楚为什么阿帕替尼的有效性在患者之间存在差异，以及什么类型的患者是治疗的候选人。在这项研究中，我们研究了阿帕替尼对13种胃癌细胞系的抗肿瘤疗效，发现它取决于细胞系。使用综合湿法和干法，我们发现阿帕替尼是c-Kit、RAF 1、VEGFR 1、VEGFR 2和VEGFR 3的多激酶抑制剂，主要抑制c-Kit。值得注意的是，在所研究的胃癌细胞系中，对阿帕替尼最敏感的KATO-III是唯一表达c-Kit、RAF 1、VEGFR 1和VEGFR 3但不表达VEGFR 2的细胞系。此外，我们确定SNW 1是一种受阿帕替尼影响的分子，在细胞存活中起着重要作用。最后，我们确定了受阿帕替尼治疗影响的SNW 1相关分子网络。这些结果表明，阿帕替尼在KATO-III细胞中的作用机制不依赖于VEGFR 2，阿帕替尼的不同疗效是由于受体酪氨酸激酶表达模式的差异。此外，我们的研究结果表明，阿帕替尼在胃细胞系中的不同疗效可能归因于稳态下的SNW 1磷酸化水平。这些发现有助于更深入地了解阿帕替尼在胃癌细胞中的作用机制。
Apatinib is known to be a highly selective vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor with anti-angiogenic and anti-tumor properties. In a phase III study, the objective response rate to apatinib was low. It remains unclear why the effectivity of apatinib varies among patients and what type of patients are candidates for the treatment. In this study, we investigated the anti-tumor efficacy of apatinib against 13 gastric cancer cell lines and found that it differed depending on the cell line. Using integrated wet and dry approaches, we showed that apatinib was a multi-kinase inhibitor of c-Kit, RAF1, VEGFR1, VEGFR2, and VEGFR3, predominantly inhibiting c-Kit. Notably, KATO-III, which was the most apatinib-sensitive among the gastric cancer cell lines investigated, was the only cell line expressing c-Kit, RAF1, VEGFR1, and VEGFR3 but not VEGFR2. Furthermore, we identified SNW1 as a molecule affected by apatinib that plays an important role in cell survival. Finally, we identified the molecular network related to SNW1 that was affected by treatment with apatinib. These results suggest that the mechanism of action of apatinib in KATO-III cells is independent of VEGFR2 and that the differential efficacy of apatinib was due to differences in expression patterns of receptor tyrosine kinases. Furthermore, our results suggest that the differential efficacy of apatinib in gastric cell lines may be attributed to SNW1 phosphorylation levels at a steady state. These findings contribute to a deeper understanding of the mechanism of action of apatinib in gastric cancer cells.