<br>使用（2S，4R）-4-[18F]FGln 进行 KRAS 突变检测，用于无创 PDAC 诊断,Molecular Pharmaceutics

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使用（2S，4R）-4-[18F]FGln 进行 KRAS 突变检测，用于无创 PDAC 诊断
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-03-08 , DOI: 10.1021/acs.molpharmaceut.4c00082
Song Liu ₁ , Futao Liu ₁ , Xingguo Hou ₁ , Qian Zhang ₁ , Ya'nan Ren ₁ , Hua Zhu ₁ , Zhi Yang ₁ , Xiaoxia Xu ₁

Affiliation

胰腺导管腺癌（PDAC）是最常见的胰腺癌类型，预后不良，症状非特异性且进展迅速。靶向 KRAS G12D 和 G12C 突变的抑制剂在 PDAC 治疗中起着关键作用。具有不同 KRAS 突变的癌细胞表现出不同程度的谷氨酰胺依赖性;特别是，具有 KRAS G12D 突变的细胞表现出谷氨酰胺摄取增加。（2S，4 R）-4-[¹⁸F]FGln 最近被开发用于临床癌症诊断和肿瘤细胞代谢分析。因此，我们通过（2S，4 R）-4-[¹⁸F]FGln 的视觉和无创方法验证了具有不同 KRAS 突变的 PDAC 模型中谷氨酰胺依赖性的异质性。注射（2S，4 R）-4-[¹⁸F]FGln 的 2 例荷瘤小鼠模型（携带 KRAS G12D 或 G12C 突变），观察和分析正电子发射断层扫描（PET）成像特征和生物分布。PANC-1 （G12D）肿瘤感兴趣区域（ROI）的 SUV_max 显著高于 MIA PaCa-2 （G12C）肿瘤。生物分布分析显示，与 MIAPaCa-2 小鼠模型相比，PANC-1 小鼠模型中（2S，4 R）-4-[¹⁸F]FGln 和其他指标（如 T/M 和 T/B）的肿瘤积累更高。总之，具有 KRAS G12D 和 G12C 突变的 PDAC 细胞表现出不同程度的（2S，4 R）-4-[¹⁸F]FGln 摄取，表明（2S，4 R）-4-[¹⁸F]FGln 可用于检测 KRAS G12C 和 G12D 突变并提供治疗指导。

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KRAS Mutation Detection with (2S,4R)-4-[18F]FGln for Noninvasive PDAC Diagnosis

Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis and nonspecific symptoms and progresses rapidly, is the most common pancreatic cancer type. Inhibitors targeting KRAS G12D and G12C mutations have been pivotal in PDAC treatment. Cancer cells with different KRAS mutations exhibit various degrees of glutamine dependency; in particular, cells with KRAS G12D mutations exhibit increased glutamine uptake. (2S,4R)-4-[¹⁸F]FGln has recently been developed for clinical cancer diagnosis and tumor cell metabolism analysis. Thus, we verified the heterogeneity of glutamine dependency in PDAC models with different KRAS mutations by a visual and noninvasive method with (2S,4R)-4-[¹⁸F]FGln. Two tumor-bearing mouse models (bearing the KRAS G12D or G12C mutation) were injected with (2S,4R)-4-[¹⁸F]FGln, and positron emission tomography (PET) imaging features and biodistribution were observed and analyzed. The SUV_max in the regions of interest (ROI) was significantly higher in PANC-1 (G12D) tumors than in MIA PaCa-2 (G12C) tumors. Biodistribution analysis revealed higher tumor accumulation of (2S,4R)-4-[¹⁸F]FGln and other metrics, such as T/M and T/B, in the PANC-1 mouse models compared to those in the MIAPaCa-2 mouse models. In conclusion, PDAC cells with the KRAS G12D and G12C mutations exhibit various degrees of (2S,4R)-4-[¹⁸F]FGln uptake, indicating that (2S,4R)-4-[¹⁸F]FGln might be applied to detect KRAS G12C and G12D mutations and provide treatment guidance.

更新日期：2024-03-08

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