International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 312 7.3 Personalized medicine approaches for KRAS-Mutant pancreatic cancer Personalized medicine approaches hold promise for improving the treatment outcomes of patients with KRAS-mutant pancreatic cancer. Targeting KRAS directly has been challenging, but recent advances in the development of covalent inhibitors targeting specific KRAS mutations, such as KRASG12C, have shown promising results in early clinical trials (Luo, 2021). Additionally, targeting downstream effectors of the KRAS signaling pathway, such as MEK and ERK, has demonstrated potential in preclinical and clinical studies (Teufel et al., 2015). Combining these targeted therapies with standard chemotherapy or other novel agents may enhance their efficacy and overcome resistance mechanisms. Future research should focus on optimizing these combination therapies and developing robust clinical trials to evaluate their effectiveness in diverse patient populations. 8 Concluding Remarks KRAS mutations are key drivers of pancreatic ductal adenocarcinoma (PDAC), present in over 90% of cases. This paper reviews the genomic mechanisms of KRAS mutations in pancreatic cancer 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. Furthermore, the interaction between KRAS mutations and other oncogenes and tumor suppressor genes exacerbates the aggressiveness of pancreatic cancer and its resistance to treatment. Although significant progress has been made in detecting and analyzing KRAS mutations, effective KRAS-targeted therapies still face considerable challenges. The high prevalence of KRAS mutations and their decisive role in pancreatic cancer progression make them critical biomarkers for diagnosis, prognosis, and treatment decision-making. The detection of KRAS mutations in liquid biopsies, particularly in circulating tumor DNA, has shown potential in monitoring disease progression and treatment response. In clinical treatment, despite some progress in KRAS-targeted therapies, resistance issues remain, indicating the need for new therapies and combination strategies to overcome these challenges. Future research should further explore the relationship between KRAS mutations and other molecular alterations to identify new therapeutic targets and biomarkers, thereby optimizing personalized treatment strategies. Although KRAS has been considered an "undruggable" target, recent studies have brought new hope for the development of KRAS-targeted therapies. The development and clinical trial results of KRASG12C inhibitors have shown potential, particularly in patients with specific KRAS mutations. However, the heterogeneity of KRAS mutations and the complexity of the tumor microenvironment continue to pose challenges for treatment. Future research directions include developing next-generation inhibitors targeting resistance mutations and exploring combination therapies to enhance efficacy. Additionally, leveraging the potential of immunotherapies and tumor vaccines may offer new treatment options for patients with KRAS-mutant pancreatic cancer. With the continuous advancement of genomic technologies and a deeper understanding of KRAS-related molecular mechanisms, KRAS-targeted therapies are expected to play a more pivotal role in the treatment of pancreatic cancer. Acknowledgments The authors extend sincere thanks to two anonymous peer reviewers for their feedback on the manuscript of this study. Funding This study is supported by the Fujian Natural Science Foundation [grant number: 2023J01755] project. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Ardalan B., Ciner A., Baca Y., Darabi S., Kasi A., Lou E., Azqueta J., Xiu J., Nabhan C., Shields A., Pishvaian M., Korn W., and Goel S., 2023, Prognostic indicators of KRASG12Xmutations in pancreatic cancer, Journal of Clinical Oncology, 41(4): 735. https://doi.org/10.1200/jco.2023.41.4_suppl.735.
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