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作者：SCI天天读
SCI
25 March 2024
Exploiting the therapeutic implications of KRAS inhibition on tumor immunity
(Cancer Cell, IF: 50.30)
Miriam Molina-Arcas and Julian Downward
CORRESPONDENCE TO: miriam.molina@crick.ac.uk, julian.downward@crick.ac.uk
SUMMARY 摘要
Over the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite the initial benefit of KRAS-G12C inhibitors for patients with tumors harboring this mutation, the rapid emergence of drug resistance underscores the urgent need to synergize these inhibitors with other therapeutic approaches to improve outcomes. RAS mutant tumor cells can create an immunosuppressive tumor microenvironment (TME), suggesting an increased susceptibility to immunotherapies following RAS inhibition. This provides a rationale for combining RAS inhibitory drugs with immune checkpoint blockade (ICB). However, achieving this synergy in the clinical setting has proven challenging. Here, we explore how understanding the impact of RAS mutant tumor cells on the TME can guide innovative approaches to combining RAS inhibition with immunotherapies, review progress in both pre-clinical and clinical stages, and discuss challenges and future directions.
在过去的十年中，RAS致癌蛋白从被认为无药物可用转变为具有两种临床批准的药物，并且目前还有几种药物处于后期开发阶段。尽管KRAS-G12C抑制剂对携带这种突变的肿瘤患者有初步的益处，但耐药性的迅速出现凸显了需要将这些抑制剂与其他治疗方法协同作用以改善结果的迫切。RAS突变肿瘤细胞可以产生免疫抑制性肿瘤微环境（TME），这表明RAS抑制后对肿瘤免疫疗法的易感性增加。这为将RAS抑制药物与免疫检查点阻断（ICB）相结合提供了理论基础。然而，在临床环境中实现这种协同作用具有挑战性。在这里，我们探讨了如何理解RAS突变肿瘤细胞TME的影响，以指导RAS抑制剂与免疫疗法相结合的创新方法，同时回顾了RAS抑制剂在临床前和临床阶段的进展，并讨论了目前存在的挑战和未来发展方向。
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