Abstract 1821: HER3 activation by MET contributes to trastuzumab resistance in HER2-positive breast cancer

Abstract Background: Trastuzumab is a standard therapy for HER2-positive breast cancer patients. Majority of the patients treated with trastuzumab in metastatic disease experience relapse. MET has been reported as one possible candidate of trastuzumab resistance however, detailed mechanism is unclear. Methods: Using panel of HER2-positive cell lines, pHER3 level was assessed with trastuzumab treatment by western blot. Co-immunoprecipitation and siRNA knockdown were used to assess the interaction between HER3 and MET. Results: Phospho-HER3 as well as pAKT levels were decreased after trastuzumab treatment in trastuzumab sensitive cell lines, while there were no deactivation in the resistant cell lines. In the primary trastuzumab resistant cell lines, 5 of 6 cells expressed MET while only one of 4 cells expressed MET in the sensitive cell lines. BT474 cells were found to have increased MET level when the cells acquired resistance to trastuzumab. HCC1954 cells, MET overexpressing and primary trastuzumab cell line, were sensitized to trastuzumab when MET was knocked down. MET knockdown led to a decrease of phosphor-HER3 level in HCC1954, BT474, and BT474 trastuzumab resistant (BT-TR) cells. The paraffin-embedded tumor samples from BT474 xenograft treated with trastuzumab and HER2-positive breast cancer patients will be stained for MET expression to assess its prognostic and predictive values sin HER2 positive breast cancer. Conclusion: MET may play a key role in maintaining HER3 phosphorylation during trastuzumab treatment and resistance in HER2 positive breast cancer. Citation Format: Kenji Hashimoto, Valentine Macaulay, Anthony Kong. HER3 activation by MET contributes to trastuzumab resistance in HER2-positive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1821. doi:10.1158/1538-7445.AM2014-1821