靶向关键的 FAK-tor：结合焦点粘附激酶(FAK)抑制剂与化疗治疗耐药非小细胞肺癌的潜力
Targeting a key FAK-tor: the therapeutic potential of combining focal adhesion kinase (FAK) inhibitors and chemotherapy for chemoresistant non-small cell lung cancer
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影响因子:4.1
分区:医学3区 / 药学2区
发表日期:2024 Nov
作者:
Emma Geijerman, Francesca Terrana, Godefridus J Peters, Dongmei Deng, Patrizia Diana, Elisa Giovannetti, Geng Xu
DOI:
10.1080/13543784.2024.2417762
摘要
非小细胞肺癌(NSCLC)是全球癌症相关死亡的主要原因，其生存率较低，主要由于NSCLC常常发展为化疗耐药。焦点粘附激酶(FAK)是一种非受体酪氨酸激酶，参与调控多种细胞过程的信号通路，包括细胞存活、迁移和肿瘤微环境(TME)，这些过程促进肿瘤进展和药物抗性。近年来，FAK抑制剂(FAKi)在NSCLC的治疗中显示出有希望的潜力。本综述旨在总结涉及FAK的关键信号通路，这些通路促进肿瘤进展和药物抗性。同时，本文也将概述目前处于临床前和早期临床试验中的FAK抑制剂在实体瘤中的应用，以及将FAK抑制剂与化疗结合的治疗潜力，因这种策略已成为克服NSCLC化疗耐药的有前景的方案。越来越明确的是，FAK并非致癌驱动因子，而是促进肿瘤进展和药物抗性的因素。因此，虽然FAK抑制剂在临床试验中单药应用仅取得有限成果，但结合其他治疗手段的FAK抑制剂方案显示出克服药物抗性的潜力。最后，具有创新意义的是FAK-PROTACs（蛋白质降解靶向嵌合物），它们能特异性靶向胞质及核内的FAK。
Abstract
NSCLC is the leading cause of cancer-related deaths globally, with a low survival rate primarily due to NSCLC frequently becoming chemoresistant. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in pathways regulating multiple processes in the cell, including survival, migration, and the TME, that contribute to both tumor progression and drug resistance. Recently, FAK inhibitors (FAKi) have shown promising potential for the treatment of NSCLC.This narrative review aims to summarize key signaling pathways involving FAK that contribute to tumor progression and drug resistance. It will further provide an overview of FAKi currently in pre- and early-phase clinical trials for solid tumors, as well as the therapeutic potential of combining FAKi with chemotherapy, as this has emerged as a promising strategy to overcome chemoresistance in NSCLC.It is becoming increasingly clear that FAK is not an oncogenic driver but rather contributes to tumor progression and drug resistance. Hence, while FAKi have only demonstrated modest results in clinical trials when given by themselves, treatment regimens combining other therapies with FAKi have shown promising potential to overcome drug resistance. Lastly, of particular novelty are FAK-PROTACs (proteolysis-targeting chimaeras), which uniquely target both cytosolic and nuclear FAK.