Targeting Nuclear EGFR: Strategies for Improving Cetuximab Therapy in Lung Cancer.

摘要

NSCLC is a deadly disease that is driven by a multitude of factors. One of these factors is the epidermal growth factor receptor (EGFR). One of the most prominent molecular targeting agents to the EGFR is the antibody cetuximab. However, most patients develop resistance to this antibody. We have found in models of cetuximab resistance that the EGFR changes its location, to the nucleus, where it is not accessible to the large antibody. Our work over the last several years has discovered how to target the nEGFR, by blocking its translocation to the nucleus through Src Family Kinase blockade. In this first year we have determined 1) that nEGFR can serve as a prognostic factor in early stage NSCLC patients., 2) we have determined that we can target nEGFR in vivo and redistribute to the membrane in vivo, a critical first step for re-sensitizing to cetuximab and 3) developed a new avenue by developing a novel EGFR mutant that lacks its transcriptional potential. This will allow us to directly test the role of nEGFR in biology and cetuximab resistance.