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异常PI3Kδ拼接异型作为潜在的生物标志物和内分泌癌症的新疗法标

Siyoung Ha¹, Himali Gujrati¹, Bi-Dar Wang^1,2

¹Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, Princess Anne, MD, United States.

Frontiers in endocrinology

|September 6, 2023

概括

这种PI3Kδ-S拼接变体驱动癌症的进展和耐药性. 准PI3Kδ-S为晚期内分泌癌症提供了一种新的策略,作为生物标志物和治疗标.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌症遗传学癌症遗传学

背景情况:

在各种癌症中,PI3K/AKT信号通路经常被上调.
异常的mRNA拼接在癌症的发展和进展中起作用.
PI3Kδ异型体涉及血液和固体瘤.

研究的目的:

研究PIK3CD-S拼接变体在内分泌和固体瘤中的作用.
评估PI3Kδ-S作为潜在的癌症生物标志物和药物标.
分析PI3Kδ异型的调节机制及其下游信号.

主要方法:

用IHC,免疫光学,西斑和RT-PCR分析患者样本和细胞系.
对PIK3CD-L和PIK3CD-S的siRNA淘汰,以评估对AKT/mTOR信号传输的影响.
操纵PTEN水平以研究其在PI3Kδ信号传递中的调节作用.
用PI3Kδ抑制剂 (Idelalisib) 和SRPK1/2抑制剂 (SRPIN340) 治疗以评估疗效.

主要成果:

PI3Kδ异型在内分泌/固体瘤中表达高.
PI3Kδ-S促进了独立于PTEN监管的AKT/mTOR信号传输.
伊德拉利西布抑制PI3Kδ-L,但不抑制PI3Kδ-S; SRPIN340逆转异常拼接和抑制信号传输.
联合治疗Idelalisib和SRPIN340在晚期瘤细胞中显示出协同效应.

结论:

PI3Kδ-S是一种致癌拼接变体,有助于晚期内分泌癌症的耐药性.
PI3Kδ-S显示出作为预后生物标志物和治疗点的潜力.
用SRPIN340针对异常拼接提供了一个新的治疗策略,特别是与PI3Kδ抑制剂结合使用.

关键词:

这是不可抗拒的阻力.在这里,我们可以看到PTEN.异常的PI3Kδ拼接异形.内分泌癌症癌症癌症精确的预后生物标志物.药物效应的协同作用

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