Cetuximab for Head and Neck Cancer from bench to clinic

Abstract

Background: Molecular targeting drugs (MTG) have proved effective for head and neck cancer (HNC) not only in basic studies but in many clinical trials. Cetuximab, an anti-EGFR monoclonal antibody, is a key drug for regimens including MTG. Cetuximab binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases and their associated downstream signalling (MAPK, PI3Kinase/Akt, STAT3 pathways) resulting in inhibition of cell survival and proliferation. Cetuximab with chemotherapy or radiotherapy is reported to be effective in preclinical studies, and combining cetuximab with chemotherapy or radiation therapy extends survival in head and neck cancer in clinical studies. However, monotherapy with cetuximab has shown limited success, although monotherapy with cetuximab is effective in preclinical studies. We focus on the fact that the evaluation of the mono administration of cetuximab in preclinical studies does not match that in clinical studies, even though the efficacy of the coadministration of cetuximab with chemotherapy or radiotherapy in preclinical studies almost matched those in clinical studies. Molecular crosstalk has been observed between EGFR and IGF1R signaling through the PI3kinase/Akt pathway, as has molecular crosstalk between the EGFR and gp130 signaling pathways through STAT3 pathway. Therefore, the combination of cetuximab with an agent that inhibits the activation of both Akt and STAT3 may overcome resistance to cetuximab in HNC. We performed a review of the literature to investigate this possibility.

Methodology: A review of the literature from 1993-2012.

Conclusions: Coadministration of cetuximab and drugs which inhibit Akt and STAT3 may significantly increase the monoadministration response rate of cetuximab. Trials suggest that the addition of drugs which inhibit Akt and STAT3 may increase efficacy to that above currently-observed synergistic effects of the coadministration of cetuximab with existing chemotherapy or radiotherapy.