International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 311 Figure 4 KRAS is dispensable for PDAC cells. KRAS inhibition activates alternative signaling pathways, such as PI3K, to promote pancreatic cancer growth Figure 5 Structural basis for resistance to KRASG12C inhibition conferred by KRASY96D(Adopted from Tanaka et al., 2021) Imagine caption: Shown are the modeled crystal structures of MRTX849 (6UT0), AMG 510 (6OIM), and ARS-1620 (5V9U) bound to KRASG12C (top) and KRASG12C/Y96D (bottom), highlighting the loss of the hydrogen bonds between MRTX849 or AMG 510 and the Y96 residue and the disruption of the switch-II pocket dynamics between ARS-1620 and KRASG12C/Y96D (Adopted from Tanaka et al., 2021) 7 Future Directions and Perspectives 7.1 Advances in genomic technologies for better understanding KRASmutations The advent of advanced genomic technologies has significantly enhanced our understanding of KRAS mutations in pancreatic cancer. Techniques such as digital droplet PCR and next-generation sequencing (NGS) have improved the sensitivity and accuracy of detecting KRAS mutations in various biological samples, including fine-needle aspiration materials and liquid biopsies (Buscail et al., 2020). These technologies not only facilitate early and precise diagnosis but also enable the monitoring of tumor dynamics and treatment responses through longitudinal assessments of circulating tumor DNA (ctDNA). Future research should focus on refining these technologies to further increase their sensitivity and specificity, as well as integrating multi-omics approaches to provide a comprehensive understanding of the molecular landscape of KRAS-mutant pancreatic cancer. 7.2 Potential biomarkers for predicting therapy response Identifying reliable biomarkers for predicting therapy response in KRAS-mutant pancreatic cancer remains a critical area of research. Studies have shown that the presence of specific KRAS mutations, such as G12D and G12V, can influence the efficacy of targeted therapies and chemotherapy (Hamidi et al., 2013). Additionally, the detection of KRAS mutations in ctDNA has been associated with prognosis and therapeutic outcomes, suggesting its potential as a predictive biomarker (Watanabe et al., 2019). Other molecular alterations, such as copy number variations and mutations in alternative MAPK pathway drivers, have also been identified as potential biomarkers for therapy response in KRAS wild-type pancreatic cancer (Singh) (Kato et al., 2023). Future research should aim to validate these biomarkers in larger clinical cohorts and explore their utility in guiding personalized treatment strategies.
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