TAM家族激酶作为癌症与免疫界面的治疗靶点

SCI

20 September 2023

TAM family kinases as therapeutic targets at the interface of cancer and immunity

(Nature Reviews Clinical Oncology, IF: 78.8)

Deborah DeRyckere, Justus M. Huelse, H. Shelton Earp，Douglas K. Graham

CORRESPONDENCE TO: douglas.graham@choa.org

Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumour immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) are potential therapeutic targets in a wide range of cancers. In cancer cells, TAM RTKs activate signalling pathways that promote cell survival, metastasis and resistance to a variety of chemotherapeutic agents and targeted therapies. TAM RTKs also function in innate immune cells, contributing to various mechanisms that suppress antitumour immunity and promote resistance to immune-checkpoint inhibitors. Therefore, TAM antagonists provide an unprecedented opportunity for both direct and immune-mediated therapeutic activity provided by inhibition of a single target, and are likely to be particularly effective when used in combination with other cancer therapies. To exploit this potential, a variety of agents have been designed to selectively target TAM RTKs, many of which have now entered clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians, including an overview of the rationale for therapeutic targeting of TAM RTKs in cancer cells and the tumour immune microenvironment, a description of the current preclinical and clinical experience with TAM inhibitors, and a perspective on strategies for continued development of TAM-targeted agents for oncology applications.

目前需要开发新的治疗方法来克服癌症细胞和肿瘤免疫微环境中对当前抗癌疗法的固有和后天耐药性机制。TAM（TYRO3、AXL和MERTK）家族受体酪氨酸激酶（RTKs）是多种癌症的潜在治疗靶点。在癌症细胞中，TAM RTK激活信号通路，促进细胞存活、转移和对多种化疗药物和靶向治疗的抵抗。TAM RTKs也在先天免疫细胞中发挥作用，参与抑制抗肿瘤免疫和促进免疫检查点抑制剂的耐药的各种机制。因此，TAM拮抗剂为通过抑制单个靶点的直接和免疫介导的治疗活性提供了前所未有的机会，并且TAM与其他癌症疗法联合使用时可能特别有效。为了开发这一潜力，已经设计了多种药物来选择性靶向TAM RTK，其中许多药物已进入临床测试。这篇综述为临床医生提供了TAM RTK的重要指南，包括对TAM RTKs在癌症细胞和肿瘤免疫微环境中的治疗靶向的基本原理进行概述，对TAM抑制剂的当前临床前经验和临床经验进行描述，以及对TAM靶向剂在肿瘤应用中持续进行开发的策略进行了展望。