Chapter 20 - MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS-mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy

Abstract

EGFR monoclonal antibodies are a new popular targeted drug for the recent clinical treatment of CRC patients. Nevertheless, patients with K-RAS mutations are resistant to it, and the therapeutic effect is significantly lower than expected, similar to cetuximab (Erbitux) and panitumumab (Vectibix). In this chapter, two MEK inhibitors (AZD6244 and AS703026) were tested in both cells and xenotransplantation to study the ability of the two drugs to respond to EGFR inhibitor resistance in patients with K-RAS mutations. Research has focused on human colorectal cancer cells, including several types that express mutant K-RAS or WT isotopes. The results showed that D-WT cells were significantly inhibited regardless of exposure to cetuximab in vivo or in vitro, including the RAS–ERK signaling pathway. Nevertheless, D-MUT cells had no noticeable abnormal changes. In contrast, the key to the effects of the two MEK inhibitors, AS703026 and AZD6244, lies in the downstream target kinase ERK of MEK, so in vivo and in vitro have a significant inhibitory effect on the proliferation of D-MUT cells. These research results pave the way for MEK inhibitors in K-RAS mutant CRC to become a mechanical preclinical concept application.