Lapatinib induces HER2 stabilization and enhances the antitumor activity of trastuzumab in vivo

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2559 Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2 amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab and studies with this combination are under way in patients. In order to dissect the differential effects of these agents given alone and in combination, we have studied receptor expression and receptor signaling and have explored a new potential mechanism underlying the profound antitumor activity that we have observed with the combination in HER2 overexpressing tumor xenografts. Lapatinib given alone or in combination with trastuzumab to HER2 overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation resulting in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation. By computational protein modelling and immunoprecipitation techniques we demonstrated that, in presence of lapatinib, the accumulation of HER2 coincided with the stabilization of inactive HER2 homo- (HER2/HER2) and heterodimers (HER2/EGFR and HER2/HER3). Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by trastuzumab were observed also in vivo , where the combination of the two agents triggered complete tumor remission after 10 days of treatment. Using an in vitro model that mimicked the effects of lapatinib in stabilizing HER2 we showed that accumulation of inactive receptor at the cell surface was sufficient to enhance immune-mediated trastuzumab-dependent cytotoxicity. These findings suggest that the inhibitory effect of lapatinib on HER2 phosphorylation can influence receptor stability and dimerization, resulting in enhanced or prolonged trastuzumab binding/activity.