Results from other groups recently reported at the 2009 annual
meeting of the American Association of Cancer Research and the American Society of Clinical Oncology confirmed these data (57). In addition to KRAS and BRAF, the EGF receptor also activates the PI3k signaling pathway. This signaling pathway can be oncogenically deregulated either by activating mutations in the PIK3CA p110 subunit or by inactivation (often by epigenetic mechanisms) of the PTEN phosphatase. The role of deregulated PIK3CA/PTEN signaling on the response to Cetuximab and Panitumab has therefore been investigated. As in one study, it is Inhibitors,research,lifescience,medical indicated that when expression of PTEN and mutations of KRAS, BRAF and PIK3CA concomitantly ascertained up to 70% of patients with mCRC unlikely to respond to anti-EGFR therapies, can be identified (58).
A gross analysis of current data regarding the impact of Inhibitors,research,lifescience,medical PIK3CA mutations and PTEN loss on response is conflicting (59-63). From the published work, it seems that PIK3CA mutations are in fact associated with the resistance, although, this correlation is nowhere close to that observed for KRAS or BRAF. However, most of the authors agree that PTEN inactivation Inhibitors,research,lifescience,medical is a negative predictor of response (59,64). As KRAS and BRAF mutations are exclusive, but the mutations of PIK3CA or inactivation of PTEN Inhibitors,research,lifescience,medical can coexist [i.e., they can occur in the same tumor containing KRAS/BRAF mutations (3).], which makes it difficult to find the individual contribution of PIK3CA mutations and PTEN inactivation to the resistance against MoAbs therapy other than KRAS and BRAF mutations. It has also been shown that PIK3CA mutations located in exon 9 and 20 hotspots exert Rigosertib different biochemical and oncologic properties and are differently activated
by KRAS (65). So, it is convincible that both PIK3CA mutations and PTEN inactivation have a little Inhibitors,research,lifescience,medical contribution of resistance against Cetuximab and Panitumumab therapy due to co-occurrence of PTEN expression and PIK3CA mutations with KRAS and BRAF mutations and different oncogentic properties of different PIK3CA mutations, so for definite conclusions more research work and analyzing of large cohorts of patients are needed to become useful to further analyze the eligible patients to treat with MoAbs therapy. However, these two markers are not yet ready to isothipendyl use clinically. Other possibilities can be the occurrence of alterations in other key elements of the EGFR-dependent signal cascade (e.g., AKT1 or MEK- MAPK), as in preclinical studies, inhibition of the MEK kinase effectively and specifically inhibits the growth of human tumor cells lines harboring activating BRAF mutations (66) and genetic alternation in tyrosine kinase receptors other than EGFR, providing an alternate pathway of survival and/or proliferation.