临床前和临床证据表明，奥希替尼-培美曲塞联合治疗具有序列依赖性协同作用，可治疗 EGFR 突变型非小细胞肺癌。
Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence.
机构信息
Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China.
Department of Respiratory Medicine, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
出版信息
J Exp Clin Cancer Res. 2022 May 3;41(1):163. doi: 10.1186/s13046-022-02369-3.
BACKGROUND
Inevitably developed resistance of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) limited its clinical benefit on non-small cell lung cancer (NSCLC). Upfront combination therapy is promising to prevent this resistance. Compelling clinical evidence indicated the failure of third-generation EGFR TKIs combined with either immunotherapy or antiangiogenic agents. In comparison, combined treatment of third-generation EGFR TKIs and chemotherapy might be a favorable choice. Herein, we systematically analyzed and compared the effects of pemetrexed and a novel third-generation EGFR TKI aumolertinib combined in different sequences, subsequently revealed the potential mechanisms and proved the optimal combination schedule with clinical retrospective study.
METHODS
Three combination schedules involving pemetrexed and aumolertinib in different sequences were developed. Their inhibition effects on cell proliferation and metastasis were firstly compared upon three human NSCLC cell lines in vitro, by cell counting kit-8, colony formation, wound healing and transwell assays respectively. Further evaluation in vivo was proceeded upon H1975 and HCC827 xenograft model. Gene and protein expression were detected by Q-PCR and western blot. Drug concentration was determined by LC-MS/MS. VEGF secretion was determined by ELISA. Tumor vessel was visualized by immunofluorescence. Lastly, a clinical retrospective study was raised with 65 patients' data.
RESULTS
The combination of pemetrexed and aumolertinib exhibited a sequence-dependent and EGFR mutant-dependent synergistic effect in vitro and in vivo. Only treatment with aumolertinib following pemetrexed (P-A) exhibited synergistic effect with stronger anti-tumor growth and anti-metastasis ability than monotherapy and also other combination sequences. This synergism could exclusively be observed in H1975 and HCC827 but not A549. Pathway analysis showed that P-A significantly enhanced the suppression of EGFR pathway. In addition, our results intriguingly found an obvious reduction of VEGF secretion and the accompanying normalization of the intratumor vessel, consequently increasing intratumoral accumulation of pemetrexed in P-A group. Finally, the clinical retrospective study verified the synergistic effect of P-A combination by significantly superior tumor response than aumolertinib monotherapy.
CONCLUSION
Aumolertinib-pemetrexed combined therapy is promising for EGFR mutant NSCLC but only in right administration sequence. P-A could become an advantageous combination strategy in clinical with synergistic inhibition of tumor growth and metastasis.
背景
第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）不可避免地产生耐药性，限制了其在非小细胞肺癌（NSCLC）中的临床获益。预先联合治疗有望预防这种耐药性。令人信服的临床证据表明，第三代 EGFR TKI 联合免疫疗法或抗血管生成药物治疗失败。相比之下，第三代 EGFR TKI 与化疗联合治疗可能是一个有利的选择。在此，我们系统地分析和比较了培美曲塞与新型第三代 EGFR TKI 奥莫替尼联合应用的不同序列的效果，随后通过临床回顾性研究揭示了潜在的机制，并证明了最佳联合方案。
方法
设计了三种不同序列的培美曲塞和奥莫替尼联合方案。通过细胞计数试剂盒-8 检测、集落形成、划痕愈合和 Transwell 检测，分别比较了三种人非小细胞肺癌细胞系中这三种联合方案对细胞增殖和转移的抑制作用。进一步在 H1975 和 HCC827 异种移植模型中进行了体内评估。通过 Q-PCR 和 Western blot 检测基因和蛋白表达。通过 LC-MS/MS 测定药物浓度。通过 ELISA 测定 VEGF 分泌。通过免疫荧光检测肿瘤血管。最后，对 65 例患者的数据进行了临床回顾性研究。
结果
培美曲塞和奥莫替尼联合应用在体外和体内均表现出序列依赖性和 EGFR 突变依赖性协同作用。只有在培美曲塞之后使用奥莫替尼（P-A）的治疗方案表现出协同作用，其抗肿瘤生长和抗转移能力强于单药治疗和其他联合方案。这种协同作用仅在 H1975 和 HCC827 中观察到，而在 A549 中则没有观察到。通路分析表明，P-A 显著增强了 EGFR 通路的抑制作用。此外，我们的结果还意外地发现，P-A 组中 VEGF 分泌明显减少，肿瘤内血管正常化，进而增加了 P-A 组中培美曲塞的肿瘤内蓄积。最后，临床回顾性研究通过明显优于奥莫替尼单药治疗的肿瘤反应证实了 P-A 联合治疗的协同作用。
结论
奥莫替尼-培美曲塞联合治疗对 EGFR 突变型 NSCLC 有应用前景，但仅限于正确的给药顺序。P-A 可能成为一种具有协同抑制肿瘤生长和转移作用的临床优势联合策略。
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