Secondary resistance to MoAbs therapies in mCRC patients is another cause of ineffectiveness, therefore, it is important to identify the possible mechanism causing secondary resistance. As has been mentioned in a clinical data, the response is transient, even in the KRAS and BRAF wild type tumors, and only last for 1 to 1.5 years (67). The somatic knocking-out or knocking-in of individual alleles in normal or neoplastic cells is a new generation of cell tumor

progression models, which has been developed recently. Generation of paired cell lines which closely recapitulate the occurrence of cancer Inhibitors,research,lifescience,medical mutations in individual patients as a result of targeting the endogenous loci for mutation or correction (68,69). Inhibitors,research,lifescience,medical It has been shown that the growth of human tumor cell lines harboring activating BRAF mutations can be inhibited by effective and specific inhibition of MEK kinase (66). Role of ethnicity, gender and smoking in BRAF mutated mCRC The link of BRAF and KRAS mutations with ethnicity has been reported. In Chinese and Caucasians BRAF

mutations were reported to be associated with advance disease stages and worse survival of papillary thyroid microcarcinoma (70,71), but not in Japanese (54). A Inhibitors,research,lifescience,medical study from Australia showed that people of southern Europe origin had a lower risk of BRAF mutation then those of Anglo-Celtic origin (72). BRAF mutations were detected in about 45% of the high microsatellite instability (MSH-H) tumors and in about 10% of the microsatellite stable (MSS) tumors in Caucasians (73). In African Americans, distinct BRAF Inhibitors,research,lifescience,medical mutation has been

reported, with 23% in MSI tumors and 0% in non-MSI tumors (74). These findings show the relation and importance of investigation of BRAF mutations with different ethnic groups. In colorectal cancers, BRAF and PIK3CA (but not KRAS, APC, or TP53) mutations display a gender bias at higher frequencies in ERK inhibitor concentration females (75,76). This suggests that tumors with BRAF somatic mutations arise from a different pathway in women. Inhibitors,research,lifescience,medical As one study has reported that exposure to estrogen in women protects against MSI, whereas, the lack of estrogen in aged females increases the risk of instability (77). Use of Hormone Replacement Therapy (HRT) significantly reduces the risk of colon cancer in postmenopausal females (78).This shows that the lack of female hormones contributes in the development of various cancers including colon cancer, which suggests that it 17-DMAG (Alvespimycin) HCl could be hypothesized that female patients with mCRC might be less likely to benefit from treatment with EGFR-targeted MoAbs. However, available clinical data do not support this hypothesis (79,80). Smoking is also associated with mCRC caused by BRAF mutations but it is not as strongly associated as gender, though females are twice likely to have a tumor with BRAF mutation, but it is not strongly associated with smoking, as men who smoke are at higher risk of mCRC with BRAF mutations (81).