Program in Cell Signaling and Metastasis, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russian Federation.
Cancer Res Commun. 2024 May 8;4(5):1227-1239. doi: 10.1158/2767-9764.CRC-23-0482.
The most common oncogenic driver mutations for non-small cell lung cancer (NSCLC) activate EGFR or KRAS. Clinical trials exploring treatments for EGFR- or KRAS-mutated (EGFRmut or KRASmut) cancers have focused on small-molecule inhibitors targeting the driver mutations. Typically, these inhibitors perform more effectively based on combination with either chemotherapies, or other targeted therapies. For EGFRmut NSCLC, a combination of inhibitors of EGFR and Aurora-A kinase (AURKA), an oncogene commonly overexpressed in solid tumors, has shown promising activity in clinical trials. Interestingly, a number of recent studies have indicated that EGFR activity supports overall viability of tumors lacking EGFR mutations, and AURKA expression is abundant in KRASmut cell lines. In this study, we have evaluated dual inhibition of EGFR and AURKA in KRASmut NSCLC models. These data demonstrate synergy between the EGFR inhibitor erlotinib and the AURKA inhibitor alisertib in reducing cell viability and clonogenic capacity in vitro, associated with reduced activity of EGFR pathway effectors, accumulation of enhanced aneuploid cell populations, and elevated cell death. Importantly, the erlotinib-alisertib combination also synergistically reduces xenograft growth in vivo. Analysis of signaling pathways demonstrated that the combination of erlotinib and alisertib was more effective than single-agent treatments at reducing activity of EGFR and pathway effectors following either brief or extended administration of the drugs. In sum, this study indicates value of inhibiting EGFR in KRASmut NSCLC, and suggests the specific value of dual inhibition of AURKA and EGFR in these tumors.
The introduction of specific KRAS G12C inhibitors to the clinical practice in lung cancer has opened up opportunities that did not exist before. However, G12C alterations are only a subtype of all KRAS mutations observed. Given the high expression of AURKA in KRASmut NSCLC, our study could point to a potential therapeutic option for this subgroup of patients.
非小细胞肺癌（NSCLC）最常见的致癌驱动突变激活 EGFR 或 KRAS。探索针对 EGFR 或 KRAS 突变（EGFRmut 或 KRASmut）癌症治疗方法的临床试验侧重于针对驱动突变的小分子抑制剂。通常，这些抑制剂与化疗药物或其他靶向疗法联合使用效果更好。对于 EGFRmut NSCLC，EGFR 和 Aurora-A 激酶（AURKA）抑制剂的联合治疗，AURKA 是一种在实体瘤中过表达的致癌基因，在临床试验中显示出有希望的活性。有趣的是，最近的一些研究表明，EGFR 活性支持缺乏 EGFR 突变的肿瘤的整体生存能力，并且 AURKA 表达在 KRASmut 细胞系中丰富。在这项研究中，我们评估了 KRASmut NSCLC 模型中 EGFR 和 AURKA 的双重抑制。这些数据表明，EGFR 抑制剂厄洛替尼和 AURKA 抑制剂alisertib 在体外降低细胞活力和集落形成能力方面具有协同作用，与 EGFR 通路效应物活性降低、增强的非整倍体细胞群积累和细胞死亡增加相关。重要的是，厄洛替尼-alisertib 联合还协同减少体内异种移植物的生长。信号通路分析表明，与单药治疗相比，厄洛替尼和 alisertib 的联合治疗在药物短暂或延长给药后降低 EGFR 和通路效应物的活性更有效。总之，这项研究表明抑制 KRASmut NSCLC 中的 EGFR 具有价值，并表明在这些肿瘤中双重抑制 AURKA 和 EGFR 的特殊价值。
特定 KRAS G12C 抑制剂在肺癌临床实践中的引入开辟了以前不存在的机会。然而，G12C 改变只是观察到的所有 KRAS 突变的一个亚型。鉴于 AURKA 在 KRASmut NSCLC 中的高表达，我们的研究可能为这组患者指出了一种潜在的治疗选择。
