School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
Molecular Horizons, University of Wollongong, Wollongong, NSW 2522, Australia.
Int J Mol Sci. 2024 May 20;25(10):5565. doi: 10.3390/ijms25105565.
The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase 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 gain-of-function mutant, -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 (IC = 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 -negative, wild-type mGAC patients.
转移性胃腺癌（mGAC）的预后仍然较差。受体酪氨酸激酶（RTK）中的基因改变，如表皮生长因子受体 及其下游效应物，包括磷脂酰肌醇 3-激酶的催化亚单位 α ，在 mGAC 中很常见。针对 RTK 和磷脂酰肌醇-3-激酶（PI3K）的治疗在其他实体瘤中已显示出临床获益，并且鉴于这些途径中存在反复改变，是针对 mGAC 进行临床开发的关键潜在靶点。此外，联合 RTK/PI3K 治疗可能克服使用单药治疗时出现的补偿机制，从而改善患者的预后。在此，我们研究了 RTK/PI3K 单药和联合药物对我们独特的人源性 mGAC 衍生的 gain-of-function 突变体、-阴性、表达 EGFR 的循环肿瘤细胞系 UWG02CTC 的反应，该细胞系在二维和三维培养条件下模拟转移的不同阶段。UWG02CTC 对靶向 PI3K p110α 亚单位的药物 PIK-75（IC = 37.0 ± 11.1 nM）或 alpelisib（7.05 ± 3.7 µM）具有高度反应性。在 3D 条件下，药物敏感性显著增加。通过联合使用 EGFR 抑制剂吉非替尼抑制 PI3K/Akt 抑制，可克服 MAPK/ERK 通路的代偿性上调，这具有强烈的协同作用。PIK-75 加吉非替尼可显著抑制 UWG02CTC 在器官样测定中的侵袭。总之，UWG02CTC 是一种强大的 mGAC 体外药物反应模型，揭示了 EGFR/PI3K 靶向药物作为 -阴性、野生型 mGAC 患者有前途的联合治疗选择。
