Elshazly Ahmed M, Xu Jingwen, Melhem Nebras, Abdulnaby Alsayed, Elzahed Aya A, Saleh Tareq, Gewirtz David A
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
Cancers (Basel). 2024 Aug 28;16(17):2989. doi: 10.3390/cancers16172989.
Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs.
酪氨酸激酶抑制剂（TKIs）是一类相对较大的小分子抑制剂，它们与ATP竞争酪氨酸激酶蛋白的催化结合位点。虽然TKIs已在多种恶性肿瘤的治疗中显示出有效性，包括慢性粒细胞白血病、胃肠道肿瘤、非小细胞肺癌和HER2过表达乳腺癌，但与几乎所有抗肿瘤药物一样，耐药性的产生常常限制了药物疗效。肿瘤细胞用于确保其在包括抗肿瘤药物在内的不同应激源下存活的一种常见生存反应是自噬。在多个肿瘤模型中，针对TKIs的自噬机制在很大程度上已被证明具有细胞保护作用，尽管在许多情况下自噬已显示出细胞毒性功能。在本综述中，我们概述了研究自噬在不同临床前肿瘤模型系统中对TKIs反应中所起作用的文献，以确定自噬抑制或调节是否可能是一种有效的辅助策略，以提高疗效和/或克服对TKIs的耐药性。
