Primary resistance to cetuximab in a panel of @entity1 -derived XXXX xenograft models: activation of MET as one mechanism for drug resistance.

@entity1 @entity1915 @entity9147 @entity7514 @entity470 @entity984 @entity5 @entity2 @entity14 @entity8497 @entity817 @entity420
Cetuximab (Erbitux  ) targets the @entity470 ( @entity470 ) and is approved for treatment of @entity14 . Despite wide expression of @entity470 , only a subgroup of @entity5 @entity1 responds to cetuximab therapy. In the present study we assessed the cetuximab response in vivo of 79 @entity1 @entity1 -derived xenografts originating from five @entity5 histotypes. We analysed basic @entity5 characteristics including @entity470 expression and activation, mutational status of @entity984 , @entity817 and @entity8497 , the expression of @entity470 ligands and the activation of @entity7514 ( @entity7514 ) and the hepatocyte growth factor receptor MET. Based on these results, a cetuximab response score including positive and negative factors affecting therapeutic response is proposed. Positive factors are high expression and activation of @entity470 and its ligands epiregulin or @entity1915 , negative factors are markers for downstream pathway activation independent of @entity470 . In cetuximab resistant @entity9147 @entity420 LXFA 526 and LXFA 1647, overexpression due to gene amplification and strong activation of MET was identified. Knock-down of MET by siRNA in the corresponding cell lines showed that anchorage-independent growth and migration are dependent on MET. MET knock down sensitized LXFA 526L and LXFA 1647L to EGF. Combined treatments of a MET inhibitor and cetuximab were additive. Therefore, combination therapy of cetuximab and a MET inhibitor in selected @entity2 @entity1 could be of high clinical significance.
