Evidence suggests cross-talk between IGF-1R and EGFR, which might be crucial for the mitogenic and transforming activity of EGFR. More specifically, the IGF-1 downstream signaling cascade is thought to induce EGFR independent PIK3CA and AKT activity, which might be another explanation for the lack of efficacy of anti-EGFR monoclonal antibodies
Inhibitors,research,lifescience,medical in KRAS WT CRC (74). This is supported by Bohula et al. in their experiments which proved that IGF-1 and IGF-2 are ubiquitously produced protein hormones that interact with the IGF-1 receptor (IGF1R) to regulate growth, differentiation, and survival. The IGF1R activates both RAS/ERK- and PI3K/AKT-related signal transduction pathways, which act to promote proliferation and prevent apoptosis (75). A phase II study with the anti-IGF-1R monoclonal antibody
IMC-A12, either alone or in combination Inhibitors,research,lifescience,medical with CTX, was performed in patients with CTX or PAM-refractory mCRC. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy and of the 21 patients treated with the combination of IMC-A12 and Inhibitors,research,lifescience,medical CTX, 1 patient with KRAS WT achieved a partial response, with disease control lasting 6.5 months. No additional antitumor activity was observed in patients with the combination treatment (76). Concomitant blockade of IGF-1R and MEK has been shown to effectively prevent the occurrence of the EGFR-IGF1R cross-talk in BRAF mutated CRC preclinical models (77). Conclusions Despite the rapid advancement in EGFR targeted therapy, much remains to be studied to understand the mechanism of resistance in CRC. Clearly, KRAS codon 12 mutation is a leading cause of resistance to EGFR inhibitors. In the KRAS WT group several contributing factors appear to Inhibitors,research,lifescience,medical influence resistance and these include ligand expression, activation of the PI3K or IGFR-1 pathways. The role of RAS codon 13 mutations and BRAF mutations as a mechanism of resistance to EGFR inhibitors is an
area that requires further research. Identification of mechanism of resistance Inhibitors,research,lifescience,medical to EGFR inhibitors will improve our ability to select patients for personalized medicine approach as well as develop new combinations of therapies that can overcome resistance to current available treatments. Acknowledgements Disclosure: The authors declare no conflict first of interest.
Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last http://www.selleckchem.com/products/DAPT-GSI-IX.html decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. 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. In contrast, the presence of BRAF mutations does not seem to have a predictive value.