KRAS: To be or not to be targeted? Biologic and computational analyses in pancreatic adenocarcinoma

Background: KRAS mutations have been shown to play a key role in pancreatic cancer progression, but little is known about the relationship between KRAS and other signaling pathways. A better definition of these pathways may help to improve targeted therapies according to the KRAS-mutation status Methods: Mutational status of KRAS gene and the correlation with the expression level of a panel of 29 genes in 91 patients with PDAC have been detected and analyzed. Survival analysis was conducted to assess the association between different KRAS mutations and/or gene expression levels. Bioinformatics analysis was carried out to predict the effect of KRAS nucleotide variations on pre-mRNA splicing, mRNA export and protein alteration Results: KRAS mutations were identified in 49 tumors (54%), whereas 42 tumors (46%) had WT KRAS genotype. Our analysis showed that Smad4 (p=0.003), Muc6 (p=0.009), VEGFR-2 (p =0.020) and VEGFB (p=0.026) were significantly more expressed in WT KRAS while SHH (p=0.012) and IHH (p=0.031) were more expressed into MT KRAS samples. Bioinformatics analysis was performed to investigate the severity of aminoacidic substitutions, showing that G-R and G-S KRAS mutations were less severe than the others. However, no significant difference in terms of overall survival was found between WT vs MT patients and comparing the different types of KRAS mutations. Conclusions: Our results suggest that the frequency of patients with PDAC who had WT KRAS tumors was higher than previously described. Patients with WT KRAS tumors may have a disease that is biologically different than those with mutated KRAS. These results suggest that patients with WT KRAS tumors may benefit from treatment with anti-angiogenic agents, whereas the use of Hedgehog inhibitors could be more effective in patients with MT KRAS tumours.