KRAS, an abbreviation for Kirsten Rat Sarcoma, is a master oncogene and the most frequently mutated RAS isoform among the three RAS isoforms (K-RAS, H-RAS, and N-RAS) [5]. The Ras protein, with KRAS being a key member, is a membrane-bound protein with inherent GTPase activity. It cycles between an inactive (GDP-bound) and active (GTP-bound) form, activated by extracellular stimuli. When in the active GTP-bound state, it activates intracellular signaling pathways crucial for cell proliferation, angiogenesis, and survival, such as the mitogen-activated protein kinase (MAPK) pathway [5].

KRAS mutations occur in approximately a quarter of all human cancers [2]. In pancreatic ductal adenocarcinomas (PDACs), the KRAS oncogene is mutated in up to 90% of cases, with the most common mutations being G12D (44%), G12V (34%), and G12R (20%) [3]. These mutations play a critical role in the initiation and maintenance of pancreatic tumors [1]. In KRAS-driven lung and pancreatic tumors, efforts have been made to validate components of the MAPK pathway as targets for treating KRAS-mutant cancers by comparing genetic information from experimental mouse models with clinical trial outcomes of selective MAPK inhibitors [2]. Additionally, KRAS-mutant cancers often co-occur with typical, cancer-type-specific mutations and have distinct gene expression signatures [4].

In conclusion, KRAS is essential for normal cellular functions related to growth and survival through its role in key signaling pathways. Its mutations are strongly associated with the development of various cancers, especially pancreatic cancer. The study of KRAS-related mouse models has been crucial in understanding the role of KRAS in cancer development and progression, providing a basis for exploring potential therapeutic strategies targeting KRAS-driven cancers [1,2,3].

References:

1. Luo, Ji. 2021. KRAS mutation in pancreatic cancer. In Seminars in oncology, 48, 10-18. doi:10.1053/j.seminoncol.2021.02.003. https://pubmed.ncbi.nlm.nih.gov/33676749/

2. Drosten, Matthias, Barbacid, Mariano. . Targeting the MAPK Pathway in KRAS-Driven Tumors. In Cancer cell, 37, 543-550. doi:10.1016/j.ccell.2020.03.013. https://pubmed.ncbi.nlm.nih.gov/32289276/

3. Stickler, Sandra, Rath, Barbara, Hamilton, Gerhard. 2024. Targeting KRAS in pancreatic cancer. In Oncology research, 32, 799-805. doi:10.32604/or.2024.045356. https://pubmed.ncbi.nlm.nih.gov/38686056/

4. Timar, Jozsef, Kashofer, Karl. . Molecular epidemiology and diagnostics of KRAS mutations in human cancer. In Cancer metastasis reviews, 39, 1029-1038. doi:10.1007/s10555-020-09915-5. https://pubmed.ncbi.nlm.nih.gov/32725342/

5. Uprety, Dipesh, Adjei, Alex A. 2020. KRAS: From undruggable to a druggable Cancer Target. In Cancer treatment reviews, 89, 102070. doi:10.1016/j.ctrv.2020.102070. https://pubmed.ncbi.nlm.nih.gov/32711246/