Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, Tamil Nadu, India.
Med Oncol. 2022 Jun 20;39(9):132. doi: 10.1007/s12032-022-01717-9.
Metabolic dysregulations have been identified as intrinsic hallmarks of cancer cells. Investigations of altered metabolic processes, in the context of the associated oncogenic signaling pathways are expected to pave way for the development of targeted cancer therapeutics. We have recently identified the enrichment of glucose and glutamine metabolism in a subset of intestinal subtype gastric tumors at the level of expression of genes, gene sets and the occurrence of metabolites. On the other hand, glucose transport, glucan and fatty acid metabolism were enriched in a subset of diffuse subtype gastric tumors. In the current study, along with glucose metabolism, mTOR, HSP90, MYC, E2F, P53 and proteasome pathways were found enriched in a subset of intestinal subtype and a part of MSI subtype gastric tumors. On the other hand, along with fatty acid metabolism, the oncogenic pathway KRAS was found to be enriched in a subset of GS tumors among diffuse subtype gastric tumors. Thus, oncogenic signaling pathways associated with two distinct metabolic rewiring which differentially occurs between major gastric cancer subtypes were identified. These pathways seem the potential targets to differentially target these gastric cancer subtypes. Exploratory integrative genomic analyses reveal HSP90 inhibitors, AKT/mTOR inhibitors, and cell cycle inhibitors as potential agents to target the gastric tumors with the rewired glucose metabolism and MEK/MAPK inhibitors as suitable drug candidates to target the diffuse subtype tumors with the dysregulated fatty acid metabolism. This observation would pave way for the selective and targeted use of signaling pathway modulators for targeted and stratified gastric cancer therapeutics.
代谢失调已被确定为癌细胞的内在特征。研究改变的代谢过程，结合相关的致癌信号通路，有望为开发靶向癌症治疗方法铺平道路。我们最近在基因、基因集和代谢物的表达水平上发现，在一部分肠型胃肿瘤中存在葡萄糖和谷氨酰胺代谢的富集。另一方面，在一部分弥漫型胃肿瘤中，葡萄糖转运、葡聚糖和脂肪酸代谢富集。在本研究中，除了葡萄糖代谢外，mTOR、HSP90、MYC、E2F、P53 和蛋白酶体途径也在一部分肠型和部分 MSI 型胃肿瘤中富集。另一方面，在一部分弥漫型胃肿瘤中，与脂肪酸代谢一起，致癌途径 KRAS 在 GS 肿瘤中富集。因此，鉴定出与两种不同代谢重排相关的致癌信号通路，这些重排在主要胃癌亚型之间存在差异。这些途径似乎是针对这些胃癌亚型的潜在靶点。探索性的综合基因组分析显示，HSP90 抑制剂、AKT/mTOR 抑制剂和细胞周期抑制剂可能是针对代谢重排的胃肿瘤的潜在药物，MEK/MAPK 抑制剂可能是针对脂肪酸代谢失调的弥漫型肿瘤的合适候选药物。这一观察结果为有选择地和有针对性地使用信号通路调节剂进行靶向和分层胃癌治疗铺平了道路。
