The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.

阿帕替尼在实体瘤治疗中的疗效已得到证实，包括非小细胞肺癌（NSCLC）。然而，阿帕替尼介导的肿瘤致死的直接功能机制和耐药的确切机制在很大程度上是未知的。在这项研究中，我们证明了阿帕替尼可以通过涉及氨基酸代谢失衡的机制重新编程人类 NSCLC 中的谷氨酰胺代谢。阿帕替尼抑制 GLS1 的表达，GLS1 是谷氨酰胺分解代谢的起始酶和限速酶。然而，代谢平衡的破坏导致氨基酸反应 (AAR) 通路的激活，称为 GCN2/eIF2α/ATF4 通路。此外，ATF4 的激活负责诱导 SLC1A5 和 ASNS，从而促进谷氨酰胺的消耗和代谢。有趣的是，阿帕替尼和 ATF4 沉默的组合消除了 NSCLC 细胞中的谷氨酰胺代谢。此外，ATF4 的敲低增强了阿帕替尼在体外和体内的抗肿瘤作用。总之，这项研究表明阿帕替尼可以通过激活人 NSCLC 细胞中的 AAR 通路来重新编程谷氨酰胺代谢，并表明靶向 ATF4 是缓解阿帕替尼耐药性的潜在治疗策略。