Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC.
胰腺癌，特别是胰腺导管腺癌（PDAC），属于致死率最高的恶性肿瘤之一，其5年生存率低于10%。最常见的KRAS突变发生在三个热点残基：甘氨酸12（G12）、甘氨酸13（G13）和谷氨酰胺61（Q61），这些突变导致Ras通路持续激活，使其成为肿瘤药物研发的主要焦点。选择性KRAS G12C抑制剂（如sotorasib、adagrasib）在临床试验中显示出中等疗效，但该突变在PDAC中发生率较低。针对KRAS G12D和G12V突变的新兴疗法，如MRTX1133、PROTACs和活性态抑制剂，在临床前研究中展现出潜力。泛RAS抑制剂如ADT-007、RMC-9805和RMC-6236等化合物可覆盖更广泛的突变类型，其疗效与安全性目前正在多项临床试验中进行评估。主要挑战在于耐药机制的出现，包括继发性突变和通路再激活。针对RAS/MAPK轴、SHP2、mTOR或SOS1的联合疗法正处于临床研究阶段。免疫疗法单药效果有限，这归因于免疫抑制性肿瘤微环境，但与KRAS靶向药物联用时可观察到协同效应。此外，KRAS突变会重编程肿瘤代谢，增强糖酵解、巨胞饮和自噬过程，这些机制正被探索作为治疗靶点。RNA干扰技术也显示出沉默突变KRAS基因并降低致瘤性的潜力。未来策略应强调靶向疗法与代谢调节剂或免疫调节剂的联合应用，以克服耐药性并提高KRAS突变PDAC患者的生存率。
Treatment of KRAS-Mutated Pancreatic Cancer: New Hope for the Patients?
肿瘤(癌症)患者之家