The pharmacological inhibition of the MAPK signaling cascade in cancer cells carrying constitutively active KRAS and BRAF mutants has been shown to improve anti-EGFR treatment with MoAbs. In this regard, it has been reported that treatment with the BRAF inhibitor, Sorafenib, can restore sensitivity to Cetuximab and Panitumumab of CRC cells carrying the V600E Inhibitors,research,lifescience,medical allele (38). So, the concomitant treatment of patients with mCRC bearing BRAF-mutated tumors, with Cetuximab/Panitumumab in combination with a BRAF inhibitor, is possible and supported by a strong rationale. MoAbs activity can be restored in BRAF mutated patients by introducing BRAF inhibitor

along with MoAbs therapy (Figure 2B). Recently

another study has reported the preclinical characterization of Vermurafenin (RG7202;PLX4032;RO5185426), which is a first-class specific small molecule BRAFV600E inhibitor in BRAF -mutated CRC cell lines Inhibitors,research,lifescience,medical and tumor xenograft models. In the Inhibitors,research,lifescience,medical same study Vermurafenin showed the dose dependent inhibition of ERK and MEK phosphorylation, which caused the inhibition of tumor growth in BRAFV600E, bearing xenograft models and arresting of cell proliferation in BRAFV600E expressing cell lines. This shows that combination of Vemurafenib with MoAbs therapy could enhance the clinical anti tumor efficacy in CRC harboring the BRAFV600E mutation (Figure 2B) (39). It has been shown that the multikinase inhibitor, Sorafenib, might restore sensitivity to EGFR inhibitors in BRAF mutated CRC cell lines, and combining of more selective BRAF inhibitors [e.g., PLX-4032 and XL-281 can also restore the sensitivity Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical EGFR-targeted antibodies towards BRAF mutation (4)]. The first generation of RAF inhibitors, including sorafenib, were notable for their lack of specificity and potency for RAF and these agents have shown limited efficacy in tumors with a high incidence of BRAF mutation, such as, melanoma. Novel inhibitors of the pathway with Dacomitinib greater selectivity for BRAF

and MEK are now in Phase 1 and 2 clinical trials with promising early results. To maximize the likelihood of success with these agents, clinical trials enriched with patients whose tumors possess BRAF and RAS mutations have been proposed (40). It has also been reported that AZ628, a selective and potent investigational small molecule RAF kinase inhibitor, is remarkably effective at inhibiting the growth of a specific subset of human cancer cell lines derived from melanomas, thyroid cancers, and colorectal cancers that harbor the BRAF V600 mutation (41). Resistance to BRAF inhibitors Clinical responses to target anticancer therapeutics are frequently confounded by de novo or acquired resistance (42).