BRAF Mutations and their Implications in Molecular Targeting Therapies for Gastrointestinal Cancers

Abstract

The epidermal growth factor receptor (EGFR) has become an important therapeutic target in gastrointestinal cancers, especially in colorectal cancer. Stimulation of the EGFR activates at least five intracellular signal cascades such as RAS/RAF/MEK(mitogen-activated ERK activating kinase)/ERK(extracellular signal-regulated kinase), PI3K (phosphatidylinositol 3-kinase) /PTEN (phosphatase and tensin homolog)/AKT(v-akt murine thymoma viral oncogene homolog), STAT (signal transducer and activator of transcription), pospholipase C, and SRC/FAK(focal adhesion kinase). These either phosphorylate their target proteins in the cytoplasm or transmit signals from growth factor receptor to the nucleus, thereby initiating subsequent expression of genes that regulate cell proliferation, differentiation, angiogenesis, and survival [1] Recently, monoclonal antibodies have been developed to target EGFR and to inhibit subsequent cellular responses. They include anti-EGFR antibodies such as cetuximab (a chimeric monoclonal immunoglobulin G1 antibody), panitumumab (a fully human monoclonal immunoglobulin G2 antibody), and trastuzumab (a monoclonal antibody against human epidermal growth factor receptor-2 (HER2) as well as inhibitors of tyrosine kinase (TK) domain of EGFR or subsequent molecules such as gefitinib, erlotinib (both inhibitors of EGFR-TK), lapatinib (a dual inhibitor of HER2-TK and EGFR-TK), sunitinib (an inhibitor of the TK of various kinds of proteins), and sorafenib (an inhibitor of RAF, a downstream molecular of RAS). Among these, cetuximab, panitumumab, and trastuzumab have received the most intensive focus of research, and their efficacy has been clearly demonstrated -especially in gastric and colorectal cancer. However, it is also a fact that this efficacy is sometimes modest as objective response rates comprise at best 50% by adding trastuzumab to chemotherapy -even among HER-2 positive gastric cancer patients [2], or between 8 and 11% by cetuximab [3,4] or pamitumumab [5,6] monotherapy in colorectal cancer patients. The efficacy is thus presumed to be restricted to a certain segment of patients. Therefore, identification of predictive markers of response and resistance in performing the EGFR targeting therapies is urgently needed to stratify those patients benefiting most from them. This in turn obviate unnecessary or futile treatment and reduce health care costs, ultimately allowing treatment to be individualized.