Serra Massimo, Rubes Davide, Schinelli Sergio, Paolillo Mayra
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
Cancers (Basel). 2023 Aug 18;15(16):4173. doi: 10.3390/cancers15164173.
Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.
转移是抗癌治疗失败的主要原因，导致患者预后不佳。要通过使癌症成为一种具有周期性但可控制复发的慢性病来提高癌症患者的预期寿命，真正的挑战在于开发专门针对转移过程中关键靶点的有效治疗策略。传统的化疗药物，如经典的烷化剂、微管抑制剂和抗代谢物，对转移细胞的疗效有限，因为它们能够选择经历上皮-间质转化（EMT）的化疗耐药细胞群体，从而促进远处部位的定植，进而维持初始的转移过程。这种情况促使人们努力寻找各种小分子和生物制剂，作为针对已知参与转移各个阶段的更特定靶点的潜在抗转移药物。在这篇简短的综述中，我们概述了与抗转移小分子重要家族相关的最新进展：细胞内酪氨酸激酶抑制剂、细胞周期蛋白依赖性激酶抑制剂、KRAS抑制剂和整合素拮抗剂。尽管这些小分子中的大多数尚未获得批准，也未在药物市场上有售，但与它们的开发阶段相关的任何信息都可能成为在与转移的持久战中识别新靶点的宝贵工具。
