Lapatinib, a Dual EGFR and HER2 Kinase Inhibitor, Selectively Inhibits HER2-Amplified Human Gastric Cancer Cells and is Synergistic with Trastuzumab In vitro and In vivo

Abstract

Purpose: HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. Lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts.Experimental Design: EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells, the combination of trastuzumab and lapatinib was evaluated using the median effects principal. The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models.Results: Lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G 1 arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G 0 -G 1 cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone.Conclusion: Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.

HER2 Amplification or Overexpression in Upper GI Tract and Breast Cancer with Clinical Diagnosis and Treatment

“…Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer Trastuzumab or other HER2 related medication on treatment of HER2 amplification gastric adenocarcinoma: Trastuzumab, a monoclonal antibody that targets HER2, induces antibody-dependent cellular cytotoxicity, inhibits HER2-mediated signaling, and prevents cleavage of the extracellular domain of HER2 [12]. Trastuzumab were found to inhibit tumor growth in gastric carcinoma cell lines, animal model and xenograft models [23,33,57,58]. Fujimoto-Ouchi (2007) used trastuzumab as a single agent inhibited the tumor growth in both of the HER2-overexpressing models but not in the HER2-negative models, GXF97 and MKN-45.…”

“…Lapatinib, small molecule kinase inhibitor: Lapatinib, binding either reversibly or irreversibly to the nucleotide-binding cleft of their target kinases, is a highly specific, reversible inhibitor that blocks the catalytic action of both HER2 and EGFR 23 . Experiments in vitro and xenograft models, established the ability of Lapatinib to inhibit both the intact form of HER2 and the truncated intracellular form (p95-HER2), which is not recognized by Trastuzumab.…”

“…In addition, Lapatinib demonstrated clinical activity and was well tolerated as first-line monotherapy in HER2-amplified, locally advanced or metastatic breast cancer [25,26]. Recently, laptinib showed a synergistic effect with trastuzumab in vitro and in vivo to inhibit HER2 amplified human gastric cancer cells and animal model [23]. Clinical phase II trial of lapatinib as first line therapy in patients with advanced or metastatic cancer showed well tolerated, which will be another potential drug to target HER2 receptors.…”

A novel gene–protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity

“…These data suggest that assessing both HER2 protein overexpression and gene amplification status may be useful for predicting the efficacy of trastuzumab therapy in gastric cancer. Several new molecularly targeted drugs against HER2 protein are currently being tested in vivo as well as in clinical studies [6][7][8], further highlighting the importance of accurate HER2 status assessment.…”

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

“…Instead, its tyrosine kinase functions via heterodimerization with other HER family members and autophosphorylation by having an extracellular domain that is always in the open conformation. Its overexpression causes increased growth, differentiation, migration, adhesion, and ultimately survival of the affected cell, leading to the final aggressiveness of the tumor [10,11]. However, despite this role in promoting tumor growth, its prognostic value in gastric adenocarcinoma is still controversial.…”