PDF(Pubmed)
Abstract：
The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.
摘要：
转移性胃腺癌（mGAC）的预后仍然较差。受体酪氨酸激酶(RTK)如表皮生长因子受体(EGFR)及其下游效应物(包括磷脂酰肌醇3-激酶(PIK3CA)的催化亚基α)的基因改变在mGAC中很常见。靶向RTK和磷脂酰肌醇-3-激酶(PI3K)治疗已经证明在其他实体瘤中的临床益处,并且考虑到这些途径中存在复发性改变,是针对mGAC的临床开发的关键潜在靶标。此外，RTK/PI3K联合治疗可以克服使用单一疗法出现的代偿机制，改善患者预后。在这里，我们研究了针对我们独特的人类mGAC衍生的PIK3CA功能获得突变体的RTK/PI3K单一和组合药物反应，人表皮生长因子受体2（HER2）阴性，表达EGFR的循环肿瘤细胞系,UWG02CTC,在二维和三维培养条件下模拟转移的不同阶段。UWG02CTC对PI3Kp110α亚基靶向药物PIK-75（IC50=37.0±11.1nM）或alpelisib（7.05±3.7µM）高度响应。药物敏感性在3D条件下显著增加。与EGFR抑制剂吉非替尼联合治疗克服了PI3K/Akt抑制引起的代偿性MAPK/ERK通路上调,这是强烈的协同作用。在器官型分析中，PIK-75加吉非替尼显着损害了UWG02CTC的侵袭。总之,UWG02CTCs是一种强大的离体mGAC药物反应模型，揭示了EGFR/PI3K靶向药物作为HER2阴性的有希望的联合治疗选择。RAS野生型mGAC患者。
