標的於RAS致癌蛋白藥物的源流與臨床上的新進展

Recent Advances in Drugs Targeting on RAS Oncoprotein and Clinical Applications

林建良(Chien-Liang Lin) ； 曹朝榮(Chao-Jung Tsao) ； 鄭高珍(Kuo-Chen Cheng) ； 黃文聰(Wen-Tsung Huang)

《內科學誌》 34卷6期 (2023/12) Pp. 458-465

https://doi.org/10.6314/JIMT.202312_34(6).05

摘要

RAS基因是促進各種癌細胞生長和產生治療抗藥性的關鍵突變基因之一。具有RAS突變基因的癌症類型很多，著名的包括胰臟癌、非小細胞肺癌和大腸直腸癌。四十年來，直接或間接抑制RAS致癌蛋白的研究，是具有挑戰性的。儘管KRAS致癌蛋白之前被認為是「不可成藥的」，但專門針對KRAS G12C突變的藥物，如sotorasib和adagrasib，在最近的臨床試驗中結果被證實有令人振奮的療效，且不良反應也很少。KRAS G12C抑制劑與Cys 12共價結合並佔據RAS的switch II pocket，導致與下游反應蛋白的結合停止。為了提高療效，將嘗試各種組合，如合併抑制EGFR/MAPK整條垂直途徑上的其他標靶藥物，合併免疫檢查點抑制劑或合併化療。除了RASG12C之外，針對RAS致癌蛋白其他熱點突變的化合物，其體外或體內的實驗正如火如荼的進行。在本綜述中，我們將討論RAS致癌蛋白相關治療策略的最新進展和其產生抗藥性的機制。

關鍵字

RAS突變（RAS mutation） ； KRAS G12C突變（KRAS G12C mutation） ； 非小細胞肺癌（Non-small cell lung cancer） ； 大腸直腸癌（Colorectal cancer） ； 胰臟癌（Pancreatic cancer）

並列摘要

RAS gene is one of the vital driver mutation genes that promote the growth and treatment resistance of various cancer types. There are many types of cancer harbored RAS mutation gene, such as pancreatic cancer, non-small cell lung cancer, and colorectal cancer. For four decades, studies of direct or indirect inhibition of RAS oncoprotein have been challenging. Though the KRAS oncoprotein has been thought as "undruggable", drugs specially targeted on KRAS G12C mutation, such as sotorasib and adagrasib, are proven promising results in clinical trials recently with less adverse effect. The KRAS G12C inhibitor binds the Cysteine-12 covalently and occupy switch II pocket of RAS, resulting in cessation of binding to downstream effector protein cascade. To improve the efficacy, various combinations are going to be tried, like other drugs targeted on the EGFR/MAPK pathway vertically, immune checkpoint inhibitor and chemotherapy. Beyond RAS G12C, compounds targeted to other hotspot mutation of RAS oncoprotein would be researched in vitro or in vivo. In this review, we will discuss recent advances in therapeutic strategy related to RAS oncoproteins and mechanism of drug resistance.