瘤性KRAS成状态对肺腺癌中的MTH1表达和8-oxodGTPase活性有不同的影响
Beatriz Mateo-Victoriano1, Govindi J Samaranayake2, Sheela Pokharel3
1Department of Radiation Oncology, Division of Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
耐RAS向治疗的肺腺癌 (LUAD) 细胞仍然需要MTH1 (8-oxodGTPase) 才能生存,特别是由于AKT信号传递,这表明MTH1是治疗点.
科学领域:
- 分子瘤学分子瘤学
- 癌症治疗方法 癌症治疗方法
- 基因组稳定性 基因组稳定性
背景情况:
- 瘤性RAS驱动肺腺癌 (LUAD),但耐药性通过适应机制出现,包括RAS成的丧失和PI3K/AKT通路过度激活.
- MTH1 (8-oxodGTPase) 阻止氧化核酸被纳入DNA,其耗尽会损害RAS驱动的LUAD中的瘤发生.
- 增加MTH1表达与LUAD患者的预后不佳相关.
研究的目的:
- 研究KRAS成者与非成者LUAD状态中MTH1表达和活动的调节.
- 确定下游信号通路 (MEK/ERK,AKT) 在MTH1监管中的作用.
- 确定MTH1作为LUAD中潜在的治疗漏洞,该漏洞已经获得了对RAS向疗法的耐药性.
主要方法:
- 在LUAD患者数据中分析MTH1表达.
- 在LUAD细胞系中操纵KRAS,MEK/ERK和AKT信号通路.
- 在各种信号条件下评估MTH1 8-oxodGTPase活性.
- 使用AMG-510 (索托拉西布) 抑制KRAS.
主要成果:
- 致癌的KRAS突变和野生型KRAS过度表达增加MTH1的表达.
- 抑制KRAS可以降低KRASG12C成的LUAD细胞中的MTH1.
- 虽然MEK/ERK信号影响MTH1水平,但AKT激活保持MTH1的高表达,特别是在KRAS非成状态.
- 增加的AKT信号维持MTH1活动,即使在低KRAScoprotein水平.
结论:
- 即使在失去KRAS依赖之后,LUAD细胞仍然需要高MTH1 8-oxodGTPase活性,这是由于AKT信号驱动的氧化还原漏洞造成的.
- MTH1代表了LUAD中一个新的,正交的漏洞,该漏洞已经对RAS向治疗产生了耐药性.
- 向MTH1可能为抗性LUAD提供新的治疗策略.
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