PO.TB04.04 · 肿瘤生物学
解码KRAS信号强度：胰腺癌肿瘤侵袭性和对RAS抑制反应的关键驱动因素
Decoding KRAS signaling intensity: A key driver of tumor aggressiveness and response to RAS inhibition in pancreatic cancer
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摘要 Abstract
中文摘要
背景：胰腺导管腺癌（PDAC）是一种高度侵袭性的恶性肿瘤，KRAS突变存在于近90%的病例中，最常见于第12和第61密码子。KRAS拷贝数增加导致KRAS信号强度升高，与不良预后和化疗反应有限相关。然而，由于缺乏合适的体内模型，KRAS信号强度在PDAC起始、进展和治疗反应中的作用仍不明确。
方法：我们通过将Pdx1-CreER(+)/Trp53(fl/fl)小鼠与Cre可诱导的Kras-LSL G12D或Kras-LSL Q61R等位基因杂交，构建了一组独特的从低到高KRAS信号水平的胰腺癌小鼠模型，这些等位基因以天然密码子（低表达）或优化密码子（高表达）表达这些致癌等位基因。系统评估了肿瘤发生、进展、转移和生存。此外，从这些模型建立了24个鼠源PDAC细胞系，并将8个人类PDAC细胞系分为低强度和高强度KRAS信号组，以评估对泛RAS抑制剂RMC-6236的治疗反应。
结果：KRAS信号强度深刻影响PDAC发生的时间、疾病进展和转移潜能。具有高、中、低KRAS信号的小鼠分别在约4-5、12-16和16-24周龄时发生PDAC。在52周期间的生存分析揭示了总体生存的显著差异，中位生存时间分别为8周（高）、23周（中）和41周（低）。值得注意的是，与中强度和低强度组相比，高强度组表现出显著更高的肺和肝远处转移率。体外治疗提示，KRAS信号强度较低的细胞往往对RMC-6236更敏感，凸显了其作为患者分层和治疗决策生物标志物的潜力。
结论：KRAS信号强度是PDAC起始、进展、转移和总体临床结局的关键决定因素。此外，它可能作为RAS靶向治疗反应的预测性生物标志物。总的来说，这些发现表明，量化KRAS信号强度可以实现精准医学方法并指导PDAC的治疗决策。本摘要使用了生成式AI工具协助文本编辑和改进。
查看英文原文 English abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, with KRAS mutations present in near 90% of cases, most frequently in codons 12 and 61. Increased KRAS copy number, resulting in elevated KRAS signaling intensity, correlates with poor prognosis and limited chemotherapy response. However, the role of KRAS signaling intensity in PDAC initiation, progression, and response to treatment remains unclear due to the lack of suitable in vivo models.
Methods: We developed a unique set of pancreatic cancer mouse models ranging from low to high levels of KRAS signaling by crossing the Pdx1-CreER (+) / Trp53 (fl/fl) mice with Cre-inducible Kras -LSL G12D or Kras -LSL Q61R alleles that either express these oncogenic alleles with native codons (low expression) or optimized codons (high expression). Tumor onset, progression, metastasis, and survival were systematically assessed. Additionally, 24 murine PDAC cell lines were established from these models, and eight human PDAC cell lines were classified into low- and high-intensity KRAS signaling groups to evaluate therapeutic response to the pan-RAS inhibitor RMC-6236.
Results: KRAS signaling intensity profoundly influences the timing of PDAC onset, disease progression, and metastatic potential. Mice with high, intermediate, and low KRAS signaling developed PDAC at approximately 4-5, 12-16, and 16-24 weeks of age, respectively. Survival analysis over a 52-week period revealed striking differences in overall survival, with median survival times of 8 weeks (high), 23 weeks (intermediate), and 41 weeks (low). Notably, the high-intensity group exhibited significantly higher rates of distant metastases to the lung and liver compared with the intermediate- and low-intensity groups. In vitro treatment suggested that cells with lower KRAS signaling intensity tended to be more sensitive to RMC-6236, highlighting its potential as a biomarker for patient stratification and therapeutic decision-making.
Conclusions: KRAS signaling intensity is a key determinant of PDAC initiation, progression, metastasis, and overall clinical outcomes. Moreover, it may serve as a predictive biomarker for response to RAS-targeted therapies. Collectively, these findings suggest that quantifying KRAS signaling intensity could enable precision medicine approaches and guide therapeutic decision-making in PDAC.Generative AI tools were used to assist with text editing and improvement of this abstract.
利益披露 Disclosure
M. Salehi, None..
S. Raji, None..
M. Ranjouri, None..
F. Chen, None..
A. Fletcher, None..
Z. Kabiri, None.