Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations.

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for non-small cell lung cancer (NSCLC) harboring EGFR mutations, but the resistance is inevitable. The drug-tolerant persister cancer cells are thought to be involved in the resistance. We recently reported that HER2 expression had a negative impact on time-to-treatment-failure in patients with EGFR mutant NSCLC. In this study, we hypothesized that HER2 might be a potential target for alternative combination therapy in NSCLC harboring EGFR mutations. In vitro study showed that the level of HER2 expression had no correlation with the sensitivity to EGFR-TKI, erlotinib but showed some correlation with HER2-inhibitor, ado-trastuzumab emtansine (T-DM1) in multiple EGFR-mutant lung cancer cell lines. In addition, HER2 expression was increased in persister cancer cells in 11-18 cell line harboring EGFR L858R or HCC827 cell line harboring EGFR exon 19 deletion after the exposure to erlotinib in vitro and in vivo. The combination of erlotinib and T-DM1 showed a superior inhibitory effect on cell proliferation compared with those of the erlotinib or T-DM1 alone in either 11-18 or HCC827 cells in vitro. The combination therapy also induced a significantly greater inhibitory effect on tumor growth in xenograft model in mice transplanted with either 11-18 or HCC827 cells compared with erlotinib alone or T-DM1 alone. No body weight loss was observed in these mice. These results suggested that the combination therapy with EGFR-TKI and T-DM1 might be a potentially promising strategy for treating lung cancer harboring EGFR mutations.

• Authors: Hiroe Kayatani, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Kazuya Nishii, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 532 Issue 3 Pg. 341-346 (11 12 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32888648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Erlotinib Hydrochloride
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine (administration & dosage)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Erlotinib Hydrochloride (administration & dosage)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mutation
• Protein Kinase Inhibitors (administration & dosage)
• Receptor, ErbB-2 (genetics)
• Xenograft Model Antitumor Assays