Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma

Abstract

Background:Lapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo.Methods:Patients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/− Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity.Results:The trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules.Conclusions:Additional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.

A framework for understanding and targeting residual disease in oncogene-driven solid cancers

“…pre-operative) trials using targeted therapy for limited time periods prior to surgical tumor resection would allow treatment to (near) maximal response followed by tumor removal. The resected tumor sample may enable extensive and multimodal characterization of residual disease following targeted therapy and allow establishment of ex vivo models, potentially circumventing the challenges of isolating adequate tumor samples from metastatic tumor biopsies in advanced-stage patients 6970 . As oncogene-targeted therapies have not yet moved from the metastatic setting to incorporation into curative-intent regimens for early-stage disease, the time is ripe to establish clinical trial protocols that will achieve these dual goals.…”

Efficacy prediction of targeted therapy for gastric cancer: The current status (Review)

“…HER2 amplification determined using HER2/CEP17 (17p11.1-q11.1) ratio and HER2 copy number may be a predictor in HER2-targeted chemotherapy, which requires verification in further prospective studies (16,17). In addition, the MET/PIK3CA/Akt pathway may be partially associated with HER2 resistance (24)(25)(26)30,31). Secondly, administration of ramucirumab, a VEGFR-2 antibody, is a standard therapy for second-line treatment of AGC (43,44).…”

“…The mesenchymal-epithelial transition (MET) pathway also serves a role in HER2-targeted drug resistance (30,31). Kim et al (30) established a lapatinib-resistant SNU216 cell line with an epithelial-mesenchymal transition (EMT) phenotype.…”

“…Therefore, this molecule may contribute to lapatinib resistance. A recent multicenter clinical trial conducted by De Silva et al (31) collected biopsy samples from patients with oesophagogastric adenocarcinoma (OGA) treated with neoadjuvant chemotherapy + lapatinib. The molecular analysis showed a significant positive correlation between MET activation and phosphor(p)-Erk level (P=0.0005) and p-PI3K/total-PI3K ratio (P=0.0037), which indicated that MET contributed to lapatinib resistance, whereas neither insulin-like growth factor receptor (IGFR) nor receptor tyrosine-protein kinase erbB-3 were associated with lapatinib resistance (31).…”

Future directions in esophageal cancer therapy

“…One study of found an increased treatment response rate among patients treated with lapatinib and chemotherapy as compared with chemotherapy alone. However, there was no significant improvement in overall survival (27,28).…”