OMS-III, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, USA.
Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, USA.
Bosn J Basic Med Sci. 2022 Sep 16;22(5):683-698. doi: 10.17305/bjbms.2021.7399.
c-kit is a classical proto-oncogene that encodes a receptor tyrosine kinase (RTK) that responds to stem cell factor (SCF). C-KIT signaling is a critical regulator of cell proliferation, survival, and migration and is implicated in several physiological processes, including pigmentation, hematopoiesis and gut movement. Accumulating evidence suggests that dysregulated c-KIT function, caused by either overexpression or mutations in c-kit, promotes tumor development and progression in various human cancers. In this review, we discuss the most important structural and biological features of c-KIT, as well as insights into the activation of intracellular signaling pathways following SCF binding to this RTK. We then illustrate how different c-kit alterations are associated with specific human cancers and describe recent studies that highlight the contribution of c-KIT to cancer stemness, epithelial-mesenchymal transition and progression to metastatic disease in different experimental models. The impact of tyrosine kinase inhibitors in treating c-KIT-positive tumors and limitations due to their propensity to develop drug resistance are summarized. Finally, we appraise the potential of novel therapeutic approaches targeting c-KIT more selectively while minimizing toxicity to normal tissue.
c-kit 是一种经典的原癌基因，编码一种细胞因子受体酪氨酸激酶（RTK），对干细胞因子（SCF）作出反应。C-KIT 信号是细胞增殖、存活和迁移的关键调节因子，涉及多种生理过程，包括色素沉着、造血和肠道运动。越来越多的证据表明，c-KIT 功能失调，无论是 c-kit 的过表达还是突变，都会促进各种人类癌症的肿瘤发生和发展。在这篇综述中，我们讨论了 c-KIT 的最重要的结构和生物学特征，以及 SCF 与该 RTK 结合后细胞内信号通路的激活机制。然后，我们说明了不同的 c-kit 改变如何与特定的人类癌症相关，并描述了最近的研究，这些研究强调了 c-KIT 对不同实验模型中癌症干细胞特性、上皮-间充质转化以及向转移性疾病进展的贡献。总结了酪氨酸激酶抑制剂在治疗 c-KIT 阳性肿瘤中的作用及其因易产生耐药性而受到的限制。最后，我们评估了更有针对性地靶向 c-KIT 而最小化对正常组织毒性的新型治疗方法的潜力。
