Tyrosine Kinase Inhibitors Are Promising Therapeutic Tools for Cats with HER2-Positive Mammary Carcinoma

Andreia Gameiro,Fernando Ferreira,Filipe Almeida,Jorge Correia,Catarina Nascimento

doi:10.3390/pharmaceutics13030346

Andreia Gameiro, Fernando Ferreira + Show 3 more

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https://doi.org/10.3390/pharmaceutics13030346

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Abstract

Feline mammary carcinoma (FMC) is a common neoplasia in cat, being HER2-positive the most prevalent subtype. In woman’s breast cancer, tyrosine kinase inhibitors (TKi) are used as a therapeutic option, by blocking the phosphorylation of the HER2 tyrosine kinase domain. Moreover, clinical trials demonstrated that TKi produce synergistic antiproliferative effects in combination with mTOR inhibitors, overcoming resistance to therapy. Thus, to uncover new chemotherapeutic strategies for cats, the antiproliferative effects of two TKi (lapatinib and neratinib), and their combination with a mTOR inhibitor (rapamycin), were evaluated in FMC cell lines (CAT-M, FMCp and FMCm) and compared with a human breast cancer cell line (SkBR-3). Results revealed that both TKi induced antiproliferative effects in all feline cell lines, by blocking the phosphorylation of EGFR members and its downstream effectors. Furthermore, combined treatments with rapamycin presented synergetic antiproliferative effects. Additionally, the DNA sequence of the her2 TK domain (exons 18 to 20) was determined in 40 FMC tissue samples, and despite several mutations were found none of them were described as inducing resistance to therapy. Altogether, our results demonstrated that TKi and combined protocols may be useful in the treatment of cats with mammary carcinomas, and that TKi-resistant FMC are rare.

Highlights

Published: 6 March 2021The feline mammary carcinoma (FMC) is one of the most common feline tumors (12%to 40% of all neoplasms) [1,2], sharing similar clinicopathological features and histologic subtypes with human breast cancer [3], making the cat a suitable model for comparative oncology studies [4,5,6,7]
Once no data is available about the use of these compounds in feline mammary carcinoma, this study aims to: (1) evaluate the antiproliferative effects of two tyrosine kinase inhibitors (TKi) using three feline mammary carcinoma cell lines
Results showed that incubation of Feline mammary carcinoma (FMC) cell lines with lapatinib or neratinib, exert potent antiproliferative effects in a dose-dependent fashion

Summary

Introduction

Published: 6 March 2021The feline mammary carcinoma (FMC) is one of the most common feline tumors (12%to 40% of all neoplasms) [1,2], sharing similar clinicopathological features and histologic subtypes with human breast cancer [3], making the cat a suitable model for comparative oncology studies [4,5,6,7]. The feline mammary carcinoma (FMC) is one of the most common feline tumors Cats with HER2-positive mammary carcinoma show a poor prognosis, with high clinical tumor aggressiveness, metastization capability and shorter overall-survival (OS) [1,2,8,9], with the overexpression of the epidermal growth factor receptor 2 (HER2) been reported in a range from 33% to 60% of all FMC cases [10]. No specific therapeutic targets are available for cats with HER2-positive mammary tumors, being the adjuvant chemotherapy unbeneficial in most of the cases, with the radical surgery being the unique therapeutic strategy [11]. The her gene is localized in the chromosome E1, presenting a sequence identity of 92% with its human counterpart [12,13]. The HER2 can dimerize with itself or with other members of the epidermal

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