Wu Lei-Lei, Jiang Wen-Mei, Liu Zhi-Yuan, Zhang Yi-Yi, Qian Jia-Yi, Liu Yu'e, Huang Yang-Yu, Li Kun, Li Zhi-Xin, Ma Guo-Wei, Xie Dong
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510030, People's Republic of China.
Discov Oncol. 2023 Jun 7;14(1):91. doi: 10.1007/s12672-023-00698-z.
The efficacy of monotherapy of AMG-510 is limited. This study explored whether the AMG-510 and cisplatin combination increases the anti-tumor effect in lung adenocarcinoma with the mutation of Kirsten rat sarcoma viral oncogene (KRAS) G12C.
Patients' data were used to analyze the proportion of KRAS G12C mutation. Besides, the next-generation sequencing data was used to uncover information about co-mutations. The cell viability assay, the concentration inhibiting 50% of cell viability (IC50) determination, colony formation, and cell-derived xenografts were conducted to explore the anti-tumor effect of AMG-510, Cisplatin, and their combination in vivo. The bioinformatic analysis was conducted to reveal the potential mechanism of drug combination with improved anticancer effect.
The proportion of KRAS mutation was 2.2% (11/495). In this cohort with KRAS mutation, the proportion of G12D was higher than others. Besides, KRAS G12A mutated tumors had the likelihood of concurrent serine/threonine kinase 11 (STK11) and kelch-like ECH-associated protein 1 (KEAP1) mutations. KRAS G12C and tumor protein p53 (TP53) mutations could appear at the same time. In addition, KRAS G12D mutations and C-Ros oncogene 1 (ROS1) rearrangement were likely to be present in one tumor simultaneously. When the two drugs were combined, the respective IC50 values were lower than when used alone. In addition, there was a minimum number of clones among all wells in the drug combination. In in vivo experiments, the tumor size reduction in the drug combination group was more than twice that of the single drug group (p < 0.05). The differential expression genes were enriched in the pathways of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt) signaling and extracellular matrix (ECM) proteoglycans compared the combination group to the control group.
The anticancer effect of the drug combination was confirmed to be better than monotherapy in vitro and in vivo. The results of this study may provide some information for the plan of neoadjuvant therapy and the design of clinical trials for lung adenocarcinoma patients with KRAS G12C mutation.
AMG-510单药治疗的疗效有限。本研究探讨了AMG-510与顺铂联合使用是否能增强对 Kirsten 大鼠肉瘤病毒癌基因（KRAS）G12C 突变的肺腺癌的抗肿瘤作用。
利用患者数据分析KRAS G12C突变的比例。此外，使用二代测序数据揭示共突变信息。进行细胞活力测定、50%细胞活力抑制浓度（IC50）测定、集落形成实验和细胞衍生异种移植实验，以探讨AMG-510、顺铂及其联合用药在体内的抗肿瘤作用。进行生物信息学分析以揭示联合用药增强抗癌效果的潜在机制。
KRAS突变比例为2.2%（11/495）。在这个有KRAS突变的队列中，G12D的比例高于其他类型。此外，KRAS G12A突变的肿瘤有同时发生丝氨酸/苏氨酸激酶11（STK11）和kelch样ECH相关蛋白1（KEAP1）突变的可能性。KRAS G12C和肿瘤蛋白p53（TP53）突变可能同时出现。此外，KRAS G12D突变和C-Ros癌基因1（ROS1）重排可能同时存在于一个肿瘤中。当两种药物联合使用时，各自的IC50值低于单独使用时。此外，联合用药组所有孔中的克隆数最少。在体内实验中，联合用药组的肿瘤体积缩小超过单药组的两倍（p < 0.05）。与对照组相比，联合用药组差异表达基因在磷脂酰肌醇3激酶-蛋白激酶B（PI3K-Akt）信号通路和细胞外基质（ECM）蛋白聚糖途径中富集。
在体外和体内均证实联合用药的抗癌效果优于单药治疗。本研究结果可为KRAS G12C突变的肺腺癌患者新辅助治疗方案的制定和临床试验设计提供一些信息。
