胰腺癌中的KRAS：从分子生物学到变革性治疗。
完整摘要 · 中文译文
胰腺导管腺癌（PDAC）是一种几乎普遍致命的恶性肿瘤，超过90%的病例中KRAS突变驱动肿瘤发生。数十年来被认为不可成药的致癌KRAS现已在多种突变亚型中实现治疗性干预，这一革命由等位基因特异性共价抑制剂引发，并因RAS(ON)多选择性抑制剂的出现而加速。daraxonrasib（一种泛RAS(ON)抑制剂）的关键3期RASolute 302试验显示，在既往治疗的转移性PDAC中，其中位总生存期较标准化疗几乎翻倍（13.2个月对6.7个月；HR 0.40；P < 0.0001）。与此同时，突变选择性G12D抑制剂（zoldonrasib、VS-7375、INCB161734）、靶向G12D的蛋白降解剂（setidegrasib）、G12C选择性RAS(ON)化合物（elironrasib）以及下一代MEK抑制剂（atebimetinib）正在推进临床评估。本综述综合了KRAS驱动的胰腺癌发生的生物学基础、突变图谱及其预后意义、KRAS抑制剂类别的结构和机制演变、近期试验的当代和新兴临床数据、毒性特征及其管理以及耐药机制。该领域正处于一个转折点：daraxonrasib现已重新定义二线PDAC管理，而daraxonrasib联合化疗的一线联合方案在早期单臂数据中产生了58%的ORR，该结果现正在随机RASolute 303试验中接受检验。未来的挑战在于转化 通过合理的联合治疗将这些结果转化为持久缓解，并克服获得性耐药。
完整摘要 · 英文原文
Pancreatic ductal adenocarcinoma (PDAC) is a near-universally lethal malignancy, with KRAS mutations driving tumorigenesis in over 90% of cases. For decades considered undruggable, oncogenic KRAS has now been therapeutically engaged across multiple mutational subtypes, a revolution precipitated by allele-specific covalent inhibitors and accelerated by the emergence of RAS(ON) multi-selective inhibitors. The pivotal phase 3 RASolute 302 trial of daraxonrasib, a pan-RAS(ON) inhibitor, demonstrated nearly doubled median overall survival (13.2 versus 6.7 months; HR 0.40; P < 0.0001) over standard chemotherapy in previously treated metastatic PDAC. Concurrently, mutation-selective G12D inhibitors (zoldonrasib, VS-7375, INCB161734), G12D-targeted protein degraders (setidegrasib), G12C-selective RAS(ON) compounds (elironrasib), and next-generation MEK inhibitors (atebimetinib) are advancing through clinical evaluation. This review synthesizes the biological basis of KRAS-driven oncogenesis in the pancreas, the mutational landscape and its prognostic implications, the structural and mechanistic evolution of KRAS inhibitor classes, contemporary and emerging clinical data from recent trials, toxicity profiles and their management, and resistance mechanisms. The field stands at an inflection point: daraxonrasib now redefines second-line PDAC management, while first-line combination regimens with daraxonrasib plus chemotherapy have produced an ORR of 58% in early-phase single-arm data, a result now being tested in the randomized RASolute 303 trial. The challenge ahead lies in translating these results into durable remissions through rational combination therapy and in overcoming acquired resistance.