Yim Juhye, Hope Chloe, Huelse Justus M, Graham Douglas K
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, GA, USA.
Expert Opin Investig Drugs. 2025 Jun;34(6):473-505. doi: 10.1080/13543784.2025.2511178. Epub 2025 May 31.
AXL, a member of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases, controls pro-tumorigenic signaling cascades and cancer-immunological functions, and promotes drug resistance. Due to AXL's multifaceted role and therapeutic activity in preclinical studies, a variety of AXL inhibitors are being developed and tested in clinical trials for cancer treatment. Some clinical studies are showing promising results for AXL inhibitors as monotherapy and in combination with standard of care therapeutics. Currently, no selective AXL-targeting therapy has reached FDA-approval, but several compounds have entered phase II and III studies.
We elaborate on the role of AXL in cancer progression and suppressing anti-cancer immunity at both the molecular level and immune cell interaction level. Additionally, we review pre-clinical and clinical data of AXL-targeting agents.
Preclinical and several early clinical trials demonstrated the safety of AXL-targeting monotherapies with some evidence of efficacy. Additionally, multiple novel combination regimens including AXL-targeting agents to overcome resistance mechanisms are being actively examined with some promising results. However, patient selection and companion biomarkers may be critical for the success of AXL-targeting therapies.
AXL是受体酪氨酸激酶TAM（TYRO3、AXL和MERTK）家族的成员，可控制促肿瘤信号级联反应和癌症免疫功能，并促进耐药性。由于AXL在临床前研究中的多方面作用和治疗活性，多种AXL抑制剂正在研发中，并在癌症治疗的临床试验中进行测试。一些临床研究表明，AXL抑制剂作为单一疗法以及与标准护理疗法联合使用均显示出有前景的结果。目前，尚无选择性靶向AXL的疗法获得美国食品药品监督管理局（FDA）批准，但有几种化合物已进入II期和III期研究。
我们详细阐述了AXL在癌症进展以及在分子水平和免疫细胞相互作用水平上抑制抗癌免疫方面的作用。此外，我们回顾了靶向AXL药物的临床前和临床数据。
临床前研究和一些早期临床试验证明了靶向AXL单一疗法的安全性，并显示出一定的疗效证据。此外，包括靶向AXL药物以克服耐药机制的多种新型联合治疗方案正在积极研究中，并取得了一些有前景的结果。然而，患者选择和伴随生物标志物可能对靶向AXL疗法的成功至关重要。
