针对ERBB3和AKT克服EML4-ALK驱动的非小细胞肺癌中的适应性抵抗
Josephina Sampson1, Hyun-Min Ju2, Nan Zhang3
1Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK. i.sampson@leeds.ac.uk.
在非小细胞肺癌 (NSCLC) 中对ALK-氨酸激酶抑制剂 (TKIs) 的耐药性可以通过向ERBB和AKT通路来克服. 双抑制增强了亡,并可能防止适应性抵抗EML4-ALK向疗法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 体微管相关的类似蛋白质的4-纳普拉斯性淋巴瘤激酶 (EML4-ALK) 融合驱动了5%的非小细胞肺癌 (NSCLC) 的瘤发生.
- ALK-氨酸激酶抑制剂 (TKIs) 是EML4-ALK阳性NSCLC的有效治疗方法,但获得的耐药性仍然是一个临床挑战.
研究的目的:
- 通过ALK TKI lorlatinib (LOR) 进行急性抑制后研究EML4-ALK阳性NSCLC细胞中的激酶反应.
- 确定潜在的治疗点,以克服在NSCLC中对ALK向疗法的耐药性.
主要方法:
- 利用了类片芯片阵列和上游激酶预测分析.
- 在洛拉提尼布治疗后检查EML4-ALK V1和V3NSCLC细胞系中的激酶反应.
- 评估了ALK与ERBB或AKT的双重抑制的影响.
主要成果:
- 在ALK-TKI治疗时,观察到化氨酸的升调,包括ERBB和AKT蛋白质.
- 双抑制ALK和ERBB/AKT破坏了RAS/MAPK和AKT/PI3K信号通路,增强了细胞灭绝.
- 耐洛拉提尼布的EML4-ALK细胞对ERBB和AKT抑制表现出敏感性.
结论:
- 在急性洛拉提尼布治疗后,AKT和ERBB3在调节信号通路方面发挥着至关重要的作用.
- 与ALK抑制剂同时向ERBB和AKT可能是预防或克服EML4-ALK阳性NSCLC适应性抵抗的可行策略.
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