International Journal of Molecular Medical Science, 2024, Vol.14, No.5, 305-314 http://medscipublisher.com/index.php/ijmms 308 through various approaches. These include the development of covalent inhibitors targeting specific KRAS mutations, such as KRASG12C, which have shown promising activity in early clinical trials. Additionally, efforts have been made to inhibit downstream effectors of KRAS, such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways (Bournet et al., 2016; Bannoura et al., 2021). Despite these efforts, the clinical efficacy of these inhibitors has been limited, necessitating the exploration of novel therapeutic strategies. Figure 1 Concentrations and abundances of KRAS mutations (Adapted from Kim et al., 2018) Image caption: Distribution of KRAS mutation concentrations and KRAS mutation fractional abundances in cfDNA according to stage (A). KRAS mutations fractional abundance (%) in tissues and cfDNA were compared in 3 stages as resectable (n = 35), locally advanced (n = 6), and metastatic groups (n = 36). The detection rate of KRAS mutations was higher in tissue DNA than in cfDNA (B). Among those groups, the metastatic group was associated with a high number of mutations. The correlation coefficient between cfDNA and tissue DNA was 0.57 (Adopted from Kim et al., 2018) Figure 2KRASmutation abundances in cfDNA according to stage. Image caption: Among three groups, the metastatic group was associated with a high number of mutations 5.2 Challenges in developing KRAS-targeted therapies Developing effective KRAS-targeted therapies has been fraught with challenges. One major obstacle is the "undruggable" nature of KRAS, which has made direct inhibition difficult (Waters and Der, 2018). Additionally, the tumor microenvironment in pancreatic cancer poses significant barriers to drug delivery and efficacy (Pei et al., 2019). Resistance mechanisms also play a critical role, as pancreatic cancer cells can activate compensatory
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