Krupa Kamila, Fudalej Marta, Włoszek Emilia, Miski Hanna, Badowska-Kozakiewicz Anna M, Mękal Dominika, Budzik Michał P, Czerw Aleksandra, Deptała Andrzej
Students' Scientific Organization of Cancer Cell Biology, Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland.
Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland.
Cancers (Basel). 2025 Jul 24;17(15):2453. doi: 10.3390/cancers17152453.
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，尤其是胰腺导管腺癌（PDAC），是最致命的恶性肿瘤之一，5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），导致Ras途径持续激活，使其成为肿瘤药物开发的主要焦点。选择性KRAS G12C抑制剂（如索托拉西布、阿达格拉西布）在临床试验中已显示出一定疗效；然而，这种突变在PDAC中并不常见。针对KRAS G12D和G12V突变的新兴疗法，如MRTX1133、PROTAC和活性状态抑制剂，在临床前研究中显示出前景。像ADT-007、RMC-9805和RMC-6236化合物这样的泛RAS抑制剂可覆盖更广泛的突变。目前正在多项临床试验中研究它们的疗效和安全性。一个主要挑战是耐药机制的发展，包括二次突变和途径重新激活。针对RAS/MAPK轴、SHP2、mTOR或SOS1的联合疗法正在进行临床研究。单独的免疫疗法显示出有限的有效性，这归因于免疫抑制性肿瘤微环境，尽管与KRAS靶向药物联合使用时会产生协同效应。此外，KRAS突变会重新编程癌症代谢，增强糖酵解、巨胞饮作用和自噬，目前正在探索针对这些方面的治疗方法。RNA干扰技术在沉默突变型KRAS和降低致瘤性方面也显示出潜力。未来的策略应强调将靶向疗法与代谢或免疫调节药物相结合，以克服耐药性并提高KRAS突变型PDAC患者的生存率。
