Adagrasib (MRTX849) 是一种已批准且有前景的 KRAS G12C 抑制剂，在治疗携带 KRAS 激活突变的晚期非小细胞肺癌 (NSCLC) 或结直肠癌 (CRC) 患者方面显示出有希望的结果。然而获得性耐药的出现限制了其长期疗效和临床应用。进一步了解获得性耐药的机制对于开发更多新的有效治疗策略至关重要。在此，我们首次发现了MRTX849获得性耐药与核因子红细胞2相关因子2（Nrf2）之间的新联系。与相应的亲代细胞系相比，Nrf2和GLS1蛋白的表达水平在具有MRTX849获得性耐药性的不同CRC细胞系中显着升高。接下来，我们发现从云南茜草根中分离出的天然环肽之一RA-V可以恢复耐药CRC细胞对MRTX849的反应。分子机制结果表明，RA-V通过泛素蛋白酶体依赖性降解抑制Nrf2蛋白，导致CRC细胞系中氧化和内质网应激以及DNA损伤的诱导。因此，RA-V 通过抑制 Nrf2/GLS1 轴来逆转 MRTX849 的耐药性，这显示出进一步发展为 MRTX849 的新型辅助疗法之一的潜力。版权所有 © 2024。由 Elsevier Ltd 出版。

Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.Copyright © 2024. Published by Elsevier Ltd.