Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
J Transl Med. 2021 May 1;19(1):184. doi: 10.1186/s12967-021-02842-1.
Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear.
Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies.
Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05).
PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.
异常的 PI3K 信号转导与曲妥珠单抗耐药的 HER2 阳性胃癌（GC）有关。PI3K 或 MEK 抑制剂在使 HER2 阳性 GC 对曲妥珠单抗敏感或克服曲妥珠单抗耐药方面的作用尚不清楚。
使用基于质谱的基因分型，我们分析了 69 名患者的胃癌肿瘤样本中 105 个热点非同义体细胞突变 PIK3CA 和 ERBB 家族（EGFR、ERBB2、ERBB3 和 ERBB4）基因。一组胃癌细胞系（N87、OE19、ESO26、SNU16、KATOIII）被用于评估对 PI3K 抑制剂 copanlisib 和 MEK1/2 抑制剂 refametinib 的抗增殖反应，以及与抗 HER2 治疗联合使用。
HER2 阳性 GC 患者的总生存期明显差于 HER2 阴性患者（15.9 个月比 35.7 个月）。PIK3CA 突变仅在 HER2 阴性肿瘤中发现，而 ERBB 家族突变在 HER2 阳性和 HER2 阴性肿瘤中均发现。Copanlisib 在 4/5 种细胞系中具有抗增殖作用，IC50 范围为 23.4（N87）至 93.8 nM（SNU16）。除 SNU16 外，所有 HER2 阳性细胞系均对 lapatinib 敏感（IC50 为 0.04µM-1.5µM）。OE19 细胞对曲妥珠单抗耐药。在 ESO-26 和 OE-19 细胞中，lapatinib 和 copanlisib 的联合具有协同作用（ED50：分别为 0.83±0.19 和 0.88±0.13），在 NCI-N87 细胞中具有相加作用（ED50：1.01±0.55）。与单独使用任何一种药物相比，copanlisib 与曲妥珠单抗的联合显著改善了 NCI-N87、ESO26 和 OE19 细胞的生长抑制作用（p<0.05）。
PI3K 或 MEK 抑制剂单独或与抗 HER2 治疗联合使用可能代表了一种改善 HER2 阳性 GC 患者治疗的策略，值得在临床试验中进一步研究。
