We previously showed that
tumor-derived
heregulin, a
ligand for HER3, is associated with both de novo and acquired resistance to
cetuximab. We have now examined whether
patritumab, a novel neutralizing
monoclonal antibody to HER3, is able to overcome such resistance. Human
colorectal cancer (DiFi) cells that are highly sensitive to
cetuximab were engineered to stably express
heregulin by retroviral
infection, and the effects of
cetuximab and
patritumab on the resulting DiFi-
HRG cells were examined. DiFi-
HRG cells released substantial amounts of
heregulin and showed resistance to
cetuximab.
Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-
HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies
cetuximab resistance in these cells. In contrast,
patritumab in combination with
cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination
therapy also inhibited the growth of DiFi-
HRG tumor xenografts in nude mice to a greater extent than did treatment with either
drug alone. Activation of HER2-HER3 signaling associated with the operation of a
heregulin autocrine loop confers resistance to
cetuximab, and
patritumab is able to restore
cetuximab sensitivity through inhibition of
heregulin-induced HER3 activation.