KRASG12V降解剂为肺腺癌提供潜在治疗机会
KRASG12V Degraders Provide a Potential Therapeutic Opportunity in Lung Adenocarcinoma.
作者
作者单位
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
摘要
中文
突变KRAS抑制已经彻底改变了肺腺癌的治疗。不幸的是，对这种靶向治疗的反应往往持续时间有限，因为耐药性的发展。靶向蛋白质降解，包括使用PROTACs（蛋白水解靶向嵌合体），提供了一种替代方法来靶向癌症中的致癌驱动因子。在本期Cancer Research中，Martín及其同事开发了一种dTAG-KRASG12V同基因小鼠模型，允许研究体内降解KRASG12V癌蛋白的效果。作者发现，降解KRASG12V癌蛋白导致所得肺腺癌肿瘤的消退。大部分消退基于癌细胞内在反应，尽管肿瘤微环境也经历了实质性重塑。尽管治疗初期有效，作者发现长期PROTAC KRAS降解剂治疗最终导致复发。对PROTAC治疗的耐药性似乎由泛素-蛋白酶体系统失调驱动，这是PROTAC降解剂活性所必需的。尽管对PROTAC降解剂产生了耐药性，所得肿瘤仍然依赖于KRAS癌蛋白，这意味着它们仍然对常规KRAS抑制剂敏感。因此，降解KRAS癌蛋白的PROTACs是治疗肺腺癌的一种有前途的方式。对PROTACs的耐药性可能不同于常规KRAS抑制剂，提示克服这种耐药性的潜在策略。参见相关文章 by Martín et al., p. 4115.
English
Mutant KRAS inhibition has revolutionized the treatment of lung adenocarcinoma. Unfortunately, responses to this form of targeted therapy are often of limited duration because of the development of resistance. Targeted protein degradation, including using PROTACs (PROteolysis-TArgeting Chimeras), presents an alternative approach to targeting oncogenic drivers in cancer. In this issue of Cancer Research, Martín and colleagues developed a dTAG-KRASG12V syngeneic mouse model that allows for the study of the effects of degrading the KRASG12V oncoprotein in vivo. The authors discovered that degrading the KRASG12V oncoprotein leads to regression of the resulting lung adenocarcinoma tumors. Most of the regression was based on cancer cell-intrinsic responses, although the tumor microenvironment also underwent substantial remodeling. Despite the initial efficacy of the treatment, the authors found that prolonged PROTAC KRAS degrader treatment eventually resulted in relapse. Resistance to PROTAC treatment seemed to be driven by dysregulation of the ubiquitin-proteasome system that is required for the activity of the PROTAC degraders. Despite developing resistance to the PROTAC degraders, the resulting tumors were still dependent on the KRAS oncoprotein, meaning that they were still sensitive to conventional KRAS inhibitors. Thus, PROTACs that degrade the KRAS oncoprotein are a promising modality for the treatment of lung adenocarcinomas. Resistance to PROTACs may differ from conventional KRAS inhibitors, suggesting potential strategies for overcoming such resistance. See related article by Martín et al., p. 4115.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区