International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 305 Feature Review Open Access KRAS Mutations in Pancreatic Cancer: Genomic Mechanisms and Therapeutic Implications Wenhai Ye, Haidan Yan Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, 350122, Fujian, China Corresponding author: joyan168@126.com International Journal of Molecular Medical Science, 2024, Vol.14, No.5 doi: 10.5376/ijmms.2024.14.0031 Received: 19 Aug., 2024 Accepted: 26 Sep., 2024 Published: 10 Oct., 2024 Copyright © 2024 Ye and Yan, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Ye W.H., and Yan H.D., 2024, KRAS mutations in pancreatic cancer: genomic mechanisms and therapeutic implications, International Journal of Molecular Medical Science, 14(5): 305-314 (doi: 10.5376/ijmms.2024.14.0031) Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal type of pancreatic cancer, with KRAS gene mutations present in over 90% of PDAC cases, serving as a major driver of the disease's progression. This study systematically reviews the genomic mechanisms of KRAS mutations and their impact on tumor initiation, progression, and therapeutic resistance. KRAS mutations promote tumor cell proliferation, invasion, and survival by activating multiple signaling pathways, such as MAPK and PI3K, and interact with other oncogenes and tumor suppressor genes, further exacerbating the aggressiveness of pancreatic cancer and its resistance to treatment. Although significant progress has been made in detecting KRAS mutations, effective targeted therapies against KRAS remain challenging. The study also explores the current status and future prospects of KRAS-targeted therapies, including novel KRAS inhibitors, combination therapies, and personalized treatment strategies. With the continuous advancement of genomic technologies, KRAS-targeted therapies are expected to play a more critical role in the treatment of pancreatic cancer. Keywords KRAS mutations; Pancreatic ductal adenocarcinoma; Targeted therapy; Genomic mechanisms; Resistance mechanisms 1 Introduction Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is one of the most lethal malignancies, with a dismal prognosis and a five-year survival rate of less than 10% (Buscail et al., 2020). Despite advancements in diagnostic techniques and therapeutic regimens, the mortality rate remains high, and PDAC is projected to become the second leading cause of cancer-related deaths within the next decade. The aggressive nature of this disease is attributed to its late presentation, rapid progression, and resistance to conventional therapies (Voutsadakis and Digklia, 2023). A hallmark of pancreatic cancer is the high prevalence of oncogenic mutations in the KRAS gene, which are present in approximately 90~95% of PDAC cases (Waters and Der, 2018). These mutations lead to the constitutive activation of the KRAS protein, which in turn drives multiple intracellular signaling pathways that promote tumorigenesis, including cell proliferation, migration, and survival. The KRAS mutation is not only a critical driver of pancreatic cancer but also a significant factor in its poor prognosis and therapeutic resistance (Luo, 2021). Recent studies have highlighted the potential of targeting KRAS and its downstream effectors as a therapeutic strategy, although effective inhibitors have yet to be successfully translated into clinical practice (Bryant et al., 2014). This study aims to provide a comprehensive analysis of the genomic mechanisms and therapeutic implications of KRAS mutations in pancreatic cancer. The study will cover the detection methods for KRAS mutations, the impact of these mutations on patient outcomes, and the potential for personalized treatment approaches based on KRAS status. By synthesizing current research findings, the study hope to elucidate the role of KRAS in the pathogenesis of PDAC, explore the diagnostic and prognostic value of KRAS mutations, evaluate emerging therapeutic strategies targeting KRAS and its associated pathways, and hope to contribute to the ongoing efforts to improve the management and treatment of pancreatic cancer.
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