PIK3CA mutations in exon 9 had no effect on survival and prognosis (40). Similar findings were seen in a review of the association between PIK3CA mutations and clinical outcomes of mCRC patients who were treated with anti-EGFR monoclonal antibodies (moAb); these results also suggest PIK3CA exon 20 may be a potential biomarker

for resistance to anti-EGFR moAbs in KRAS WT mCRC (55). PIK3CA mutations have been associated with resistance to the anti-EGFR therapy since they can coexist with KRAS mutations; however it has been difficult to establish a definitive one-on-one relationship. Inhibitors,research,lifescience,medical Hot-spot mutations in PIK3CA mutations, specifically www.selleckchem.com/products/Vandetanib.html helical and kinase domain mutations, may novel operate by different Inhibitors,research,lifescience,medical but synergistic mechanisms independent of KRAS (56). However the role of PIK3CA mutation in EGFR resistance in mCRC patients remains controversial. A study of PIK3CA in a group of 200 chemo-refractory

mCRC patients who were treated with CTX in KRAS WT patients found no difference in CTX response in relation to PIK3CA status (57). PIK3CA mutations were detected in 16.4%. Only PIK3CA mutations occasionally coexisted with other gene mutations. In univariate Inhibitors,research,lifescience,medical analysis, prognostic significance for survival was seen for BRAF mutations codon 12-only KRAS mutations, high amphiregulin mRNA expression only in KRAS WT CRC, and high epiregulin mRNA Inhibitors,research,lifescience,medical expression regardless of KRAS mutation status. Favorable predictive factors were: high amphiregulin mRNA in KRAS WT tumors, high epiregulin mRNA, and low Ephrin A2 receptor mRNA. CTX-treated patients with amphiregulin-low KRAS WT CRC fared very poorly, with survival similar to KRAS mutant disease. Patients with KRAS

codon 13 or other non-codon 12 mutations had a median survival similar to that of patients with KRAS WT; this is in contrast to patients with KRAS codon 12 mutations who did worse than all others (58). In terms of targeting treatment approaches, KRAS mutations Inhibitors,research,lifescience,medical show evidence of resistance to P13K pathway inhibitors (59). Specifically the presence of the mutant KRAS predicted resistance in the presence of the P13K inhibitor, PX-866 (60). This may limit the utility of single-agent Drug_discovery P13K pathway inhibitors which have KRAS and PIK3CA mutations seen in colon cancers (61). PTEN Enhanced P13K signaling is often due to the activation of genes involved in the P13K pathway such as PIK3CA and AKT1, or loss of phosphatase and tensin homolog (PTEN) (62-64). Mutations in PTEN were seen in approximately 18% of patients with CRC tumors who had MSI suggesting that defective mismatch repair of PTEN may be a possible target for future therapies (65,66). Additional data suggests that PTEN promoter hypermethylation occurred frequently with high versus low MSI (19.1% vs. 2.2%; P=0.002) (67).