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受体酪氨酸激酶抑制剂的最新进展:靶向癌症治疗中充满前景的中流砥柱

Recent developments in receptor tyrosine kinase inhibitors: A promising mainstay in targeted cancer therapy.

作者信息

Kumar Rahul, Goel Harsh, Solanki Raghu, Rawat Laxminarayan, Tabasum Saba, Tanwar Pranay, Pal Soumitro, Sabarwal Akash

机构信息

Dr B. R. A.-Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.

School of Life Sciences, Central University of Gujarat, Gandhinagar, India.

出版信息

Med Drug Discov. 2024 Sep;23. doi: 10.1016/j.medidd.2024.100195. Epub 2024 Jul 1.

Abstract

During the past two decades, significant advances have been made in the discovery and development of targeted inhibitors aimed at improving the survival rates of cancer patients. Among the multitude of potential therapeutic targets identified thus far, Receptor Tyrosine Kinases (RTKs) are of particular importance. Dysregulation of RTKs has been implicated in numerous human diseases, particularly cancer, where aberrant signaling pathways contribute to disease progression. RTKs have a profound impact on intra and intercellular communication, and they also facilitate post-translational modifications, notably phosphorylation, which intricately regulates a multitude of cellular processes. Prolonged phosphorylation or the disruption of kinase regulation may lead to significant alterations in cell signaling. The emergence of small molecule kinase inhibitors has revolutionized cancer therapy by offering a targeted and strategic approach that surpasses the efficacy of traditional chemotherapeutic drugs. Over the last two decades, a plethora of targeted inhibitors have been identified or engineered and have undergone clinical evaluation to enhance the survival rates of cancer patients. In this review, we have compared the expression of different RTKs, including Met, KDR/VEGFR2, EGFR, BRAF, BCR, and ALK across different cancer types in TCGA samples. Additionally, we have summarized the recent development of small molecule inhibitors and their potential in treating various malignancies. Lastly, we have discussed the mechanisms of acquired therapeutic resistance with a focus on kinase inhibitors in EGFR mutant and ALK-rearranged non-small cell lung cancer and BCR-ABL positive chronic myeloid leukemia.

摘要

在过去二十年中,在发现和开发旨在提高癌症患者生存率的靶向抑制剂方面取得了重大进展。在迄今为止确定的众多潜在治疗靶点中,受体酪氨酸激酶(RTK)尤为重要。RTK的失调与多种人类疾病有关,尤其是癌症,其中异常信号通路促进疾病进展。RTK对细胞内和细胞间通讯有深远影响,还促进翻译后修饰,特别是磷酸化,它精细地调节多种细胞过程。长时间的磷酸化或激酶调节的破坏可能导致细胞信号的显著改变。小分子激酶抑制剂的出现彻底改变了癌症治疗,提供了一种靶向且有策略的方法,其疗效超过传统化疗药物。在过去二十年中,已鉴定或设计出大量靶向抑制剂,并已进行临床评估以提高癌症患者的生存率。在本综述中,我们比较了TCGA样本中不同癌症类型中不同RTK的表达,包括Met、KDR/VEGFR2、EGFR、BRAF、BCR和ALK。此外,我们总结了小分子抑制剂的最新进展及其在治疗各种恶性肿瘤中的潜力。最后,我们讨论了获得性治疗耐药的机制,重点是EGFR突变和ALK重排的非小细胞肺癌以及BCR-ABL阳性慢性髓性白血病中的激酶抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43cc/11393807/538c8f3da213/nihms-2019570-f0001.jpg

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