School of Pharmacy, Bengbu Medical College, Bengbu, China.
School of Pharmacy, Bengbu Medical College, Bengbu, China; Anhui Province Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China.
Eur J Pharmacol. 2023 Apr 15;945:175571. doi: 10.1016/j.ejphar.2023.175571. Epub 2023 Feb 17.
Aumolertinib is an irreversible third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), although it has been administered for the treatment of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). However, it is unclear whether aumolertinib combined with ionizing radiation (IR) has potential therapeutic effects in treating brain metastases (BM) tumors from NSCLC. This study explored the anti-tumor effects of aumolertinib combined with IR in epidermal growth factor receptor mutated (EGFRm) NSCLC BM tumors. First, we established a xenograft model of NSCLC BM tumors in BALB/c nude mice and assessed the anti-tumor effects of this combination. Furthermore, we examined the concentrations of aumolertinib in brain tissue and blood using liquid chromatography-mass spectrometry (LC-MS); after that, we used CCK-8, colony formation, flow cytometry assay, and immunofluorescence staining to detect the effects of aumolertinib combined with IR upon PC-9 and NCI-H1975 cells, such as cell proliferation, survival, apoptosis, cycle distribution, the situation of DNA damage, and the expression levels of relevant proteins which were detected via western blotting; finally, we chose a clinical case with which to explore the clinical benefits to the EGFRm NSCLC BM patient after the treatment of the aforementioned combination. The experiments of NSCLC BM tumor animal models demonstrated that the combination enhanced the therapeutic effects and increased the intracranial accumulation of aumolertinib; the combination can inhibit cell proliferation and survival, delay the repair of DNA damage, and increase the rates of cell apoptosis and aumolertinib abrogated G2/M phase arrest, which the IR induced; the clinical study verified that the combination demonstrated better patient benefits. In conclusion, our study demonstrated that combining aumolertinib and IR has promising anti-tumor effects in EGFR-mutant NSCLC and that this combined treatment modality may be employed as a potential therapeutic strategy for EGFR-mutant NSCLC BM patients clinically.
奥莫替尼是一种不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），尽管它已被用于治疗表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）。然而，奥莫替尼联合电离辐射（IR）是否对治疗非小细胞肺癌脑转移（BM）肿瘤具有潜在的治疗效果尚不清楚。本研究探讨了奥莫替尼联合 IR 对表皮生长因子受体突变型（EGFRm）NSCLC BM 肿瘤的抗肿瘤作用。首先，我们建立了 BALB/c 裸鼠 NSCLC BM 肿瘤的异种移植模型，并评估了该联合治疗的抗肿瘤效果。此外，我们使用液相色谱-质谱（LC-MS）检测了脑组织和血液中的奥莫替尼浓度；之后，我们使用 CCK-8、集落形成、流式细胞术和免疫荧光染色检测了奥莫替尼联合 IR 对 PC-9 和 NCI-H1975 细胞的影响，如细胞增殖、存活、凋亡、细胞周期分布、DNA 损伤情况以及通过蛋白质印迹检测的相关蛋白表达水平；最后，我们选择了一个临床病例，以探索该联合治疗对 EGFRm NSCLC BM 患者的临床获益。NSCLC BM 肿瘤动物模型实验表明，该联合增强了治疗效果，并增加了奥莫替尼在颅内的蓄积；该联合可以抑制细胞增殖和存活，延迟 DNA 损伤的修复，并增加细胞凋亡率，奥莫替尼阻断了 IR 诱导的 G2/M 期阻滞；临床研究验证了该联合治疗具有更好的患者获益。总之，我们的研究表明，奥莫替尼联合 IR 对 EGFR 突变型 NSCLC 具有有前景的抗肿瘤作用，这种联合治疗模式可能成为 EGFR 突变型 NSCLC BM 患者的潜在治疗策略。
