Abstract 289: MET activation mediates lapatinib resistance in experimental esophageal adenocarcinoma

Abstract

Introduction: A major target for esophageal adenocarcinoma (EAC) therapies is the human epidermal growth factor receptor 2 (HER2). Unfortunately, patients treated with lapatinib, a dual EGFR and HER2 inhibitor, frequently develop resistance. Lapatinib fails to improve patient survival in HER2-postive EAC, and the mechanisms contributing to resistance remain largely unknown. Recent studies have demonstrated that HER2 and MET receptor tyrosine kinases are co-overexpressed in a subset EAC. In this study, we therefore studied the role of MET activation in lapatinib resistance mechanisms in experimental EAC. Methods: We first characterized MET and HER2 activation in a panel of human EAC cell lines, and the differential susceptibility of these EAC cell lines to single agent or combination of MET and HER2 inhibitions by foretinib and lapatinib, respectively. We then explored the antitumor efficacy with survival advantage following foretinib and lapatinib monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. We also tested MET and HER activation status with sensitivity to their inhibitors in newly generated lapatinib resistant OE19 EAC cells (OE19-LPR). Results: The OE33 EAC cell line with phosphorylation of both MET and HER2, demonstrated reduced sensitivity to foretinib and lapatinib when used as single agents. The co-administration of foretinib and lapatinib effectively inhibited both MET and HER2 phosphorylation, synergistically inhibited cell proliferation and xenograft tumor growth, induced apoptosis, and significantly enhanced overall mouse survival, thus overcoming single agent resistance. In the OE19 EAC cell line with only HER2 phosphorylation and the ESO51 EAC cell line with only MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent with lack of enhanced growth inhibition when the two agents were combined. Interestingly, OE19-LPR cells showed significant upregulated expression of phosphorylated MET compared to parent OE19 cells, detected by both Activesignal assay and Western blot analysis. In addition, OE19-LPR cells showed significantly reduced sensitivity to lapatinib compared to parent OE19 cells, and the co-administration of foretinib and lapatinib synergistically inhibited cell proliferation in OE19-LPR cells. Conclusion: These data suggest that resistance to HER2 targeted therapies in HER2 and MET overexpressed EAC cells can be due to MET activation. Thus MET and HER2 targeted therapy appears to be a sensible treatment strategy for HER2 positive MET-overexpressing EAC. Citation Format: Md Sazzad Hassan, Fiona Williams, Lucia Petrova, Niranjan Awasthi, Margaret Schwarz, Roderich Schwarz, Urs von Holzen. MET activation mediates lapatinib resistance in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 289.

Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: A systematic review

“…As reported by multiple studies, MET was upregulated and phosphorylated in cells treated with lapatinib, afatinib, or trastuzumab, or in cells demonstrating secondary resistance to these anti-HER2 agents. Thus, MET upregulation contributes to drug resistance by maintaining downstream signaling and stimulating cell cycle progression in vitro [48][49][50][51][52][53][54][55]. These results are supported by sequencing results of HER2positive GEA patients specimens, showing upregulation and amplification of MET in untreated and trastuzumab-treated specimens [46,47].…”

“…Another major mechanism which could contribute to anti-HER2 resistance is upregulation of alternative receptors. Whilst prooncogenic signaling through HER2 is blocked by targeting the HER2 receptor, activation and upregulation of alternative receptors such as HER3 and MET compensate by increased dimerization with HER2 and maintaining downstream signaling, respectively [42][43][44][45][46][47][48][49][50][51]57,58,118]. Previous (pre)clinical literature demonstrated synergistic effects of the addition of pertuzumab to trastuzumab.…”

“…In response to HER2 targeting, other receptors can compensate for HER2 loss by maintaining activation of shared downstream pathways. Ten studies demonstrated MET receptor upregulation following inhibition of the HER2 receptor in resistant models [46][47][48][49][50][51][52][53][54][55], whilst others described the contributions of other ErbB receptor family members (n = 7) [28,37,46,[56][57][58][59], fibroblast growth factor receptors (FGFR) (n = 4) [34,[60][61][62], or other receptors (n = 6) [36,52,61,[63][64][65].…”

“…(A) Overexpression, downregulation, modification, or degradation of the HER2 receptor reduce anti-HER2 treatment sensitivity, such as trastuzumab, pertuzumab, lapatinib, and T-DM1 [27][28][29][30][31][32][33][34][35]44,45]. (B) Upon HER2 downregulation, upregulation of other receptors activate the PI3K/AKT and MAPK pathways via Src kinase [28,34,36,37,[46][47][48][49][50][51][52][53][54][55][56][58][59][60][61][62][63][64][65]88]. (C) Upregulation of EGFR and subsequent STAT3 activation result in mucin upregulation, preventing compound binding to the HER2 receptor [36][37][38].…”