曲妥珠单抗联合西妥昔单抗在耐药胃癌中的抗肿瘤作用及其机理.docVIP

解放军医学院硕士学位论文 英文摘要 Anti-tumor activity of trastuzumab in combination with cetuximab in trastuzumab?resistant gastric cancer and its mechanism of action Abstract Gastric cancer is one of the most common malignant carcinomas worldwide, and it has the second highest cause of cancer death. Researchs show that about 15% - 45% of gastric cancer patients with HER2 overexpression. Trastuzumab，a humanized monoclonal antibody directed against the dimerization interfaces in domain IV of HER2, has currently been approved for clinical treatment in patients with erbB2-positive metastatic gastric and gastro-esophageal junction cancer. Clinical data showed that clinical response rate of trastuzumab reachs almost 30%, but half of the trastuzumab-responsive patients develop resistance a year after treatment. Thus, futher studies are needed to better understand other signal transduction pathways of acquired resistance after long-term exposure to trastuzumab in gastric cancers. Identification of mechanism for acquired resistance will lead to design of clinical trials with newer approaches to delay or reverse resistance. The ErbB family belongs to the type I receptor tyrosine kinases and includes EGFR (HER1), ErbB2(Her2), ErbB3(HER3) and ErbB4 (HER4). ErbB family members are activated by various ligands except HER2, which may not have physiological ligands. Although HER2 is unable to bind to any ligand, it could form homodimers or heterodimers with both ligand-free and ligand-bound forms of EGFR、HER3 or HER4 and therefore becomes activated and triggers potent mechanisms of cell proliferation and survival. It has been reported that EGFR receptors activate various common signaling pathways including Ras/Raf/MEK/ERK and PI3K/AKT. Recent studies have highlighted that prolonged treatment with trastuzumab may induce tumor cells to reprogram 5 万方数据 解放军医学院硕士学位论文 themselves by overexpressing various receptor tyrosine kinases (RTKs) to develop alternative compensatory pathways to sustain cell prol