Targeting a key FAK-tor: the therapeutic potential of combining focal adhesion kinase (FAK) inhibitors and chemotherapy for chemoresistant non-small cell lung cancer.

IF 4.9 2区 医学 Q1 PHARMACOLOGY & PHARMACY Expert opinion on investigational drugs Pub Date : 2024-10-22 DOI:10.1080/13543784.2024.2417762
Emma Geijerman, Francesca Terrana, Godefridus J Peters, Dongmei Deng, Patrizia Diana, Elisa Giovannetti, Geng Xu
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Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

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靶向关键的FAK-tor:结合焦点粘附激酶(FAK)抑制剂和化疗治疗化疗耐药非小细胞肺癌的治疗潜力。
简介非小细胞肺癌是全球癌症相关死亡的主要原因,其生存率低的主要原因是非小细胞肺癌经常出现化疗耐药。病灶粘附激酶(FAK)是一种非受体酪氨酸激酶,参与调节细胞的多个过程,包括生存、迁移和TME,这些过程都会导致肿瘤进展和耐药性。最近,FAK 抑制剂(FAKi)显示出治疗 NSCLC 的巨大潜力:本综述旨在总结涉及FAK的关键信号通路,这些通路有助于肿瘤的进展和耐药性的产生。它将进一步概述目前正在进行的FAKi治疗实体瘤的前期和早期临床试验,以及FAKi与化疗相结合的治疗潜力,因为这已成为克服NSCLC化疗耐药性的一种有前途的策略:越来越清楚的是,FAK 并非致癌驱动因素,而是导致肿瘤进展和耐药性的因素。因此,虽然FAKi本身在临床试验中的效果一般,但将其他疗法与FAKi相结合的治疗方案却显示出克服耐药性的巨大潜力。最后,FAK-PROTACs(蛋白水解靶向chimaeras)具有特殊的新颖性,可同时靶向细胞膜和细胞核FAK。
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来源期刊
CiteScore
10.00
自引率
0.00%
发文量
71
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Investigational Drugs (ISSN 1354-3784 [print], 1744-7658 [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles and original papers on drugs in preclinical and early stage clinical development, providing expert opinion on the scope for future development. The Editors welcome: Reviews covering preclinical through to Phase II data on drugs or drug classes for specific indications, and their potential impact on future treatment strategies Drug Evaluations reviewing the clinical and pharmacological data on a particular drug Original Research papers reporting the results of clinical investigations on agents that are in Phase I and II clinical trials The audience consists of scientists, managers and decision-makers in the pharmaceutical industry, and others closely involved in R&D.
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