针对关键FAK-TOR：结合焦点粘附激酶（FAK）抑制剂的治疗潜力和化学疗法化学疗法
Targeting a key FAK-tor: the therapeutic potential of combining focal adhesion kinase (FAK) inhibitors and chemotherapy for chemoresistant non-small cell lung cancer
影响因子:4.10000
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
摘要
NSCLC是全球癌症相关死亡的主要原因，其存活率较低，主要是由于NSCLC经常变得化学抗性。局灶性粘附激酶（FAK）是一种非受体酪氨酸激酶，参与调节细胞中多个过程的途径，包括存活，迁移和TME，既有助于肿瘤进展和耐药性。最近，FAK抑制剂（FAKI）显示出对NSCLC治疗的有希望的潜力。此叙述性综述旨在总结涉及FAK的关键信号通路，涉及FAK，这些FAK有助于肿瘤进展和耐药性。 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.因此，尽管Faki仅在临床试验中表现出适度的结果，但将其他疗法与Faki结合的治疗方案显示出有望克服耐药性的潜力。最后，特别是新颖的是FAK-PROTAC（涉及蛋白水解的嵌合体），它们唯一地靶向胞质和核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.