PO.ET07.01 · 实验与分子治疗
多聚异戊二烯化半胱氨酰胺抑制剂抑制生长，诱导多种KRAS突变肺癌细胞的细胞骨架和转录组重塑
Polyisoprenylated cysteinyl amide inhibitors suppress growth, induce cytoskeletal and transcriptomic remodeling in multiple KRAS -mutated lung cancer cells
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摘要 Abstract
中文摘要
肺癌仍是全球癌症相关死亡的主要原因，KRAS突变驱动约30%的病例。尽管KRAS G12C蛋白抑制剂如Sotorasib和Adagrasib已改善治疗结果，但内在耐药和突变异质性（如KRAS G12A）限制了它们的长期疗效。因此，迫切需要能够靶向多种突变KRAS变体的新型药物。多聚异戊二烯化半胱氨酰胺抑制剂（PCAIs）是G蛋白（如KRAS、RHOA、CDC42和RAC1）必需的翻译后修饰的分子模拟物，这些修饰对于它们作为功能性蛋白复合物一部分的相互作用很重要。PCAIs被设计用于干扰和破坏KRAS信号所需的多聚异戊二烯化依赖性蛋白-蛋白相互作用。在此，我们评估了PCAIs（NSL-YHJ-2-27）与Adagrasib和Sotorasib相比对NCI-H23（通常携带突变型KRAS G12C）及其中KRAS G12C被KRAS G12A替换的衍生物的长期效应。用3 µM Adagrasib或NSL-YHJ-2-27处理携带KRAS G12C的NCI-H23显示出一致的细胞增殖抑制，分别下降82%和87%。然而，3 µM的Adagrasib仅抑制携带KRAS G12A的NCI-H23增殖19%，而Sotorasib几乎无效。同时，NSL-YHJ-2-27抑制携带KRAS G12A的NCI-H23达88%。Sotorasib处理的突变型KRAS G12C NCI-H23的增殖在连续处理第18天反弹至54%，表明KRAS G12C突变体可快速适应以耐受Sotorasib。NSL-YHJ-2-27抑制携带KRAS G12C或KRAS G12A的NCI-H23的活力，相应的EC 50值分别为2.0和2.5 µM。2 µM的NSL-YHJ-2-27和Adagrasib破坏F-肌动蛋白丝，增加细胞变圆，并分别使平均细胞面积减少89%和92%。Sotorasib显示平均细胞面积略微减少15%。对NSL-YHJ-2-27处理的携带KRAS G12C的NCI-H23细胞进行的转录组分析揭示三个显著上调的基因和两个下调的基因。促凋亡基因如CXCL2、WNT9A、PTX3分别升高9、12和10倍，而运动和血管生成相关基因如TMSB15A和POSTN分别下调30和9倍。通路富集突显了细胞骨架组织、粘附和KRAS相关信号网络的改变。这些发现支持PCAIs作为有前景的泛突变KRAS靶向肺癌治疗候选药物。
查看英文原文 English abstract
Lung cancer remains the leading cause of cancer-related deaths globally, with KRAS mutations driving approximately 30% of cases. Although KRAS G12C protein inhibitors such as Sotorasib and Adagrasib have improved therapeutic outcomes, intrinsic resistance and mutation heterogeneity such as KRAS G12A limit their long-term efficacy. Therefore, novel agents capable of targeting multiple mutant KRAS variants are urgently needed. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are molecular mimics of the essential post-translational modifications of G-proteins such as KRAS, RHOA, CDC42, and RAC1 that are important for their interactions as part of functional protein complexes. PCAIs were designed to interfere with and disrupt the polyisoprenylation-dependent protein-protein interactions required for KRAS signaling. Here we evaluated the long-term effects of PCAIs (NSL-YHJ-2-27), versus Adagrasib and Sotorasib on NCI-H23, which normally carries mutant KRAS G12C , and a derivative in which KRAS G12C was replaced by KRAS G12A . Treatment of NCI-H23 carrying KRAS G12C with 3 µM Adagrasib or NSL-YHJ-2-27 showed consistent inhibition of cell proliferation, down by 82 and 87% respectively. However, Adagrasib at 3 µM inhibited proliferation of NCI-H23 carrying KRAS G12A by just 19%, while Sotorasib had little to no effect. At the same time NSL-YHJ-2-27 inhibited NCI-H23 carrying KRAS G12A by 88%. Proliferation of Sotorasib-treated mutant KRAS G12C NCI-H23 rebounded to 54% by day 18 of continuous treatment, showing KRAS G12C mutants can quickly adapt to resist Sotorasib. NSL‑YHJ-2-27 inhibited the viability of NCI-H23 carrying either KRAS G12C or KRAS G12A , with respective EC 50 values of 2.0 and 2.5 µM. NSL-YHJ-2-27 and Adagrasib at 2 µM disrupted F-actin filaments, increased cell rounding, and reduced mean cell area by 89 and 92%, respectively. Sotorasib showed a slight decrease in mean cell area of 15%. Transcriptomic profiling of NSL-YHJ-2-27-treated NCI-H23 cells carrying KRAS G12C revealed three genes that were significantly upregulated and two that were downregulated. Proapoptotic genes such as CXCL2, WNT9A, PTX3 were elevated by 9, 12 and 10-fold, whereas motility and angiogenesis-associated genes such as TMSB15A and POSTN were downregulated by30 and 9-fold, respectively. Pathway enrichment highlighted alterations in cytoskeletal organization, adhesion, and KRAS-associated signaling networks. These findings support PCAIs as promising pan-mutant-KRAS-targeting therapeutic candidates against lung cancer.
利益披露 Disclosure
D. Kwakye, None..
C. Lilly, None..
K. Ofosu-Asante, None..
J. F. Odoom, None..
J. K. Ablordeppey, None..
N. Lamango, None.