These include the RAS-RAF-MAPK axis, which is PD0332991 mainly involed in cell proliferation, and the P13K-PTEN-AKT pathway, which is involved in cell survival and motility (30). Figure 1 A. Normal binding of ligand to EGFR and activation of downstream signaling transduction cascade leading to DNA synthesis,cellular proliferation and migration

etc; B. Binding of anti-EGFR drug e.g., cetuximab or panitumumab to EGFR which inhibits ligand … The anti-EGFR monoclonal antibody, Cetuximab, has demonstrated clinical beneifits in, and is widely used to treat, mCRC (Figure 1) (31). Notion has been acknowledged by European Medicine Agency (EMEA), which approved the use of Panitumumab or Cetuximab only Inhibitors,research,lifescience,medical in mCRC patients whose tumors display wt-KRAS (32). American Society of Clinical Oncology recommended that only those mCRC patients with wild-type KRAS be

considered candidates to receive anti-EGFR therapy. The efficacy of Inhibitors,research,lifescience,medical anti-EGFR monoclonal antibodies in 60-70% of mCRC patients with wt-KRAS tumors is still limited, with response rates between 10 and 40% (33). There is a need for additional biomarkers for these patients. Interestingly Inhibitors,research,lifescience,medical the expression of the EGFR protein has not been strongly associated with clinical response to Cetuximab in CRC, although, there is limited evidence that amplification of the EGFR gene relates to objective response and other indices of clinical benefits. The relation between the increase of the EGFR gene dosage and response to Cetuximab Inhibitors,research,lifescience,medical or Panitumumab is not strong enough to allow the clinical use of this biomarker for the predictive selection of patients (34). As proven, BRAF is the principal effectors

of KRAS (35) and its oncogenic V600E mutation is mutually exclusive with KRAS mutations in CRCs (36). It has been demonstrated that the V600E Inhibitors,research,lifescience,medical mutation can also preclude responsiveness to Panitumumab or Cetuximab in mCRC patients and cellular models of CRC also, mutations in BRAF have shown impaired responsiveness to Panitumumab or Cetuximab in patients with mCRC (Figure 2A) (4). Of note, KRAS and BRAF mutations are known to be mutually exclusive in colorectal cancers (36). Patients who have mutated BRAF don’t respond to MoAbs therapy even if they only present wt-KRAS, which shows that wt-BRAF is required to respond to MoAbs therapy to treat mCRC (4). Therefore, mutated BRAF tumors (approximately 10%) add algebraically to those carrying KRAS mutations (35-45%), thus further empowering the selection of patients eligible for Cetuximab/Panitumumab treatment. Of note, when considered together, the two biomarkers can identify up to 55% non-responders (4). Figure 2 A. Inactivation of EGFR by anti-EGFR drugs does not inhibit the activation of RAS-MAPK pathway due to BRAF oncogene mutation, shown in red, which causes uncontrolled cellular proliferation, migration, and survival etc; B. Combination of cetuximab/panitumumab …