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胰腺癌发生发展的分子机制与靶向治疗策略
DOI: 10.12449/JCH260234
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：刘铁鑫负责设计论文框架，起草论文；郭松雨负责论文修改；王震侠负责拟定写作思路，指导撰写文章并最后定稿。
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摘要: 胰腺癌恶性程度高，5年生存率不足10%，其分子机制以Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变（90%）、肿瘤蛋白p53/细胞周期蛋白依赖性激酶抑制因子2A/SMAD家族成员4失活及表观遗传异常（DNA甲基化、非编码RNA等）为核心，驱动肿瘤进展。近年来，靶向治疗取得突破，如KRAS原癌基因甘氨酸12→半胱氨酸突变抑制剂（Sotorasib、Adagrasib）和非共价KRAS原癌基因甘氨酸12→半胱氨酸突变抑制剂的临床应用；针对表皮生长因子受体、DNA修复（多腺苷二磷酸核糖聚合酶抑制剂）及免疫微环境（靶向程序性细胞死亡受体1及其配体联合疗法）的策略也显著提升疗效。然而，耐药性与肿瘤异质性仍是挑战。未来需结合精准医疗和联合疗法以改善预后。Abstract: Pancreatic cancer （PC） has a high degree of malignancy and a 5-year survival rate of <10%， with the core molecular mechanisms of Kirsten rat sarcoma viral oncogene homolog （KRAS） mutations （90%）， inactivation of tumor protein p53/cyclin-dependent kinase inhibitor 2A/SMAD family member 4， and epigenetic dysregulation （including DNA methylation and non-coding RNA alterations）， which promotes the progression of PC. In recent years， breakthroughs have been made in targeted therapy， including the clinical application of KRASG12C inhibitors （sotorasib， adagrasib） and KRASG12D inhibitors， and the strategies targeting epidermal growth factor receptor， DNA repair （PARP inhibitors）， and immune microenvironment （combined therapies targeting PD-1 and PD-L1） have significantly improved the treatment outcome of PC. Nevertheless， drug resistance and tumor heterogeneity remain huge challenges. Precision medicine and combined therapies should be adopted in the future to improve the prognosis of patients.
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Key words:
- Pancreatic Neoplasms /
- KRAS mutation /
- Epigenomics /
- Molecular Targeted Therapy
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注： MAPK，丝裂原活化蛋白激酶；PI3K，磷脂酰肌醇3激酶；KRAS，Kirsten大鼠肉瘤病毒癌基因同源物；TP53，肿瘤蛋白p53；CDKN2A，细胞周期蛋白依赖性激酶抑制因子2A；SMAD4，SMAD家族成员4；PARP，多腺苷二磷酸核糖聚合酶；EGFR，表皮生长因子受体；CAF，癌症相关成纤维细胞；PRC2，多梳抑制复合物2； RNAPⅡ，RNA聚合酶Ⅱ；SAM，S-腺苷甲硫氨酸。百分数表示相应基因或蛋白发生突变或失调的概率。
图 1 胰腺癌发病机制图
Figure 1. Schematic diagram of the pathogenesis of pancreatic cancer
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