School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P.R. China.
Theranostics. 2022 Jan 1;12(3):1321-1332. doi: 10.7150/thno.67889. eCollection 2022.
KRAS mutations are one of the most common gene mutations linked to cancer, presenting in approximately 25% of all tumors, especially pancreatic, lung, and colorectal cancers. Mutant KRAS has long been considered an undruggable target, stalling progress in direct KRAS targeting for many years, while targeted drug delivery into KRAS mutant cells utilizing their transformed metabolic behavior might present an alternative opportunity. Macropinocytosis, a nonselective, fluid-phase, endocytic route, was found to be upregulated as a metabolic feature in KRAS-driven tumors and plays a critical role in nutrient acquisition from extracellular fluids. With the observation that a variety of drug delivery systems could be internalized by KRAS mutant cancer cells through macropinocytosis, exploiting macropinocytosis for intracellular delivery of therapeutics into KRAS mutant tumor cells is emerging as a new drug delivery expedition. In this article, we summarized cancer biology studies that examined KRAS mutation-induced macropinocytosis, reviewed recent studies exploiting macropinocytosis enhancement for KRAS mutant cancer cell-selective drug delivery, and discussed the potential opportunities, challenges and pitfalls of this strategy.
KRAS 突变是与癌症相关的最常见基因突变之一，约存在于所有肿瘤的 25%，尤其是胰腺、肺和结直肠肿瘤。突变型 KRAS 长期以来被认为是一个不可成药的靶点，多年来阻碍了直接针对 KRAS 的药物研发，而利用其转化的代谢行为将靶向药物递送到 KRAS 突变细胞中可能提供了另一种机会。巨胞饮作用是一种非选择性的、流体相的、内吞途径，被发现作为 KRAS 驱动的肿瘤中的代谢特征而上调，并在从细胞外液中获取营养物质方面发挥关键作用。观察到各种药物递送系统可以通过巨胞饮作用被 KRAS 突变的癌细胞内化，利用巨胞饮作用将治疗剂递送到 KRAS 突变的肿瘤细胞中是一种新的药物递送策略。本文总结了研究 KRAS 突变诱导的巨胞饮作用的癌症生物学研究，综述了最近利用巨胞饮作用增强进行 KRAS 突变癌细胞选择性药物递送的研究，并讨论了该策略的潜在机会、挑战和陷阱。
