PIK3CA mutations and/or PTEN loss have been shown to predict response in some (70-73) but not all studies (74,75). These studies are all limited by small numbers and often a lack of validation for correlative testing. The largest study to date with 1,022 tumor

Protease Inhibitor Library cell assay samples showed only PIK3CA mutations in exon 20 (constituting the kinase domain) to be predictive of response but not mutations Inhibitors,research,lifescience,medical in exon 9 (the helical domain). About 20% of PI3KCA mutations were located in exon 20 while 68.5% were located in exon 9. The investigators did not look at PTEN expression (76). These results suggest that alterations in the PIK3/Akt/mTor pathway may be responsible for some of the patients who do not respond to EGFR inhibitors initially. Inhibitors,research,lifescience,medical A few groups have specifically looked at mechanisms of resistance in patients who have progressed on an EGFR inhibitor. Montagut et al. found two out of 10 patients who had progressed on cetuximab to have a mutation in the EGFR ectodomain (S492R) which prohibits binding of cetuximab but not panitumumab (77). Misale et al. performed KRAS gene deep sequencing on tumors from patients who had progressed on an EGFR inhibitor and found secondary KRAS mutations in 6 out of 10 cases suggesting that this could either be acquired mutations on therapy or the selection of pre-existent KRAS mutant clones (78). Inhibitors,research,lifescience,medical IGF-1R is upregulated in 50-90% of mCRC and has been

Inhibitors,research,lifescience,medical associated with poor prognosis. Cells with an altered IGF-1R pathway seem to escape EGFR inhibitor mediated cell death by activation of the PI3K pathway by heterodimerization of IGF-1R with EGFR. Overexpression of IGF-1 has been associated with resistance to cetuximab in KRAS wild-type tumors (79). HER3 is overexpressed in 30-80% of metastatic CRC and has been associated with Inhibitors,research,lifescience,medical EGFR

inhibitor resistance (80). Its effects are mediated through the PI3K/Akt pathway. MET overexpression is found in most mCRC, both in KRAS wild-type and KRAS mutant tumors and interacts with the EGFR pathway to promote growth of CRC cells (81). Preclinical evidence suggests that coupling of MET with HER3 may lead to sustained activation of PI3K/Akt pathway in lung cancer cell lines, thereby bypassing the inhibited EGFR (82). Furthermore, it is possible that resistance to EGFR inhibitors could result from a selection of clones already resistant to the drugs. It is therefore oxyclozanide clear that several different mechanisms may signal resistance through the PI3K/Akt pathway and extend survival of the cancer cell. This is currently an active area of ongoing research. Summary EGFR inhibitors are an important addition to the growing armamentarium in metastatic colorectal cancer. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit.