Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
Cancer Chemother Pharmacol. 2013 Apr;71(4):1095-100. doi: 10.1007/s00280-013-2110-4. Epub 2013 Feb 19.
The role of v-ATPases in cancer biology is being increasingly recognized. Yeast studies indicate that the tyrosine kinase inhibitor imatinib may interact with the v-ATPase genes and alter the course of cancer progression. Data from humans in this regard are lacking.
We constructed 55 lymphoblastoid cell lines from pedigreed, cancer-free human subjects and treated them with IC20 concentration of imatinib mesylate. Using these cell lines, we (i) estimated the heritability and differential expression of 19 genes encoding several subunits of the v-ATPase protein in response to imatinib treatment; (ii) estimated the genetic similarity among these genes; and (iii) conducted a high-density scan to find cis-regulating genetic variation associated with differential expression of these genes.
We found that the imatinib response of the genes encoding v-ATPase subunits is significantly heritable and can be clustered to identify novel drug targets in imatinib therapy. Further, five of these genes were significantly cis-regulated and together represented nearly half-log fold change in response to imatinib (p = 0.0107) that was homogenous (p = 0.2598).
Our results proffer support to the growing view that personalized regimens using proton pump inhibitors or v-ATPase inhibitors may improve outcomes of imatinib therapy in various cancers.
v-ATPase 在癌症生物学中的作用正逐渐得到认识。酵母研究表明，酪氨酸激酶抑制剂伊马替尼可能与 v-ATPase 基因相互作用，改变癌症进展的过程。这方面来自人类的数据尚缺乏。
我们从无癌症的家系人类受试者中构建了 55 个淋巴母细胞系，并以伊马替尼甲磺酸盐的 IC20 浓度对其进行处理。使用这些细胞系，我们：（i）评估了编码 v-ATPase 蛋白的几个亚基的 19 个基因对伊马替尼治疗的遗传性和差异表达；（ii）估计了这些基因之间的遗传相似性；（iii）进行了高密度扫描，以寻找与这些基因差异表达相关的顺式调节遗传变异。
我们发现，编码 v-ATPase 亚基的基因对伊马替尼的反应具有显著的遗传性，可以进行聚类，以确定伊马替尼治疗中的新药物靶点。此外，其中 5 个基因明显受到顺式调控，共同代表了对伊马替尼反应的近半对数倍变化（p = 0.0107），且具有同质性（p = 0.2598）。
我们的结果支持这样一种观点，即使用质子泵抑制剂或 v-ATPase 抑制剂的个体化治疗方案可能会改善各种癌症中伊马替尼治疗的效果。
