Abstract
Simple SummaryMammary tumors are common in cats, presenting an aggressive behavior with high tumor recurrence. Therefore, new and efficient therapeutic protocols are urgent. Monoclonal antibodies (mAbs; ADC) are widely used in human breast cancer therapy, inhibiting the HER2 dimerization and leading to cell apoptosis. Furthermore, drug combinations, with tyrosine kinase inhibitors (TKi) are valuable in patients’ therapeutic protocols. In this study, two mAbs, and an ADC, as well as combined protocols between mAbs and mAbs plus lapatinib (TKi) were tested to address if the drugs could be used as new therapeutic options in feline mammary tumors. All the compounds and the combined treatments revealed valuable antiproliferative effects, and a conserved cell death mechanism, by apoptosis, in the feline cell lines, where the mutations found in the extracellular domain of the HER2 suggest no immunotherapy resistance.Feline mammary carcinoma (FMC) is a highly prevalent tumor, showing aggressive clinicopathological features, with HER2-positive being the most frequent subtype. While, in human breast cancer, the use of anti-HER2 monoclonal antibodies (mAbs) is common, acting by blocking the extracellular domain (ECD) of the HER2 protein and by inducing cell apoptosis, scarce information is available on use these immunoagents in FMC. Thus, the antiproliferative effects of two mAbs (trastuzumab and pertuzumab), of an antibody–drug conjugate compound (T-DM1) and of combined treatments with a tyrosine kinase inhibitor (lapatinib) were evaluated on three FMC cell lines (CAT-MT, FMCm and FMCp). In parallel, the DNA sequence of the her2 ECD (subdomains II and IV) was analyzed in 40 clinical samples of FMC, in order to identify mutations, which can lead to antibody resistance or be used as prognostic biomarkers. Results obtained revealed a strong antiproliferative effect in all feline cell lines, and a synergistic response was observed when combined therapies were performed. Additionally, the mutations found were not described as inducing resistance to therapy in breast cancer patients. Altogether, our results suggested that anti-HER2 mAbs could become useful in the treatment of FMC, particularly, if combined with lapatinib, since drug-resistance seems to be rare.
Highlights
To human breast cancer [1], the feline mammary carcinoma (FMC) is a very common tumor [2], presenting different molecular subtypes [3], being the feline HER2-positive, the most prevalent one (33–60%) [2,4]
This study aims to: (1) evaluate the antiproliferative effects of the monoclonal antibodies (mAbs) and of the T-DM1 in three feline carcinoma cell lines (CAT-MT, FMCm and FMCp); (2) characterize the HER2 expression in the feline cell lines and identify the existence of genomic mutations in the feline her2 extracellular domain (ECD); (3) describe the cell death mechanism induced by the mAbs and T-DM1, in the carcinoma cell lines; (4) evaluate the synergistic antiproliferative effects by the combination of mAbs
Cell cultures were maintained at 37 ◦C, in a humidified atmosphere of 5% (v/v) CO2 (Nuaire, Plymouth, MN, USA), in Dulbecco’s Modified Eagle Medium (DMEM; Corning, New York, NY, USA), for CAT-MT and SKBR-3, whereas FMCm and FMCp cell lines were maintained in Roswell Park Memorial Institute 1640 Medium (RPMI; Corning), both supplemented with heat-inactivated 20% (v/v) fetal bovine serum (FBS; Corning)
Summary
To human breast cancer [1], the feline mammary carcinoma (FMC) is a very common tumor [2], presenting different molecular subtypes [3], being the feline HER2-positive, the most prevalent one (33–60%) [2,4]. HER2 is a transmembrane glycoprotein, which modulates cell proliferation, differentiation and survival [9,10]. This protein is composed by three domains: an extracellular domain (ECD), a short transmembrane region and an intracellular tyrosine kinase (TK) activity domain [9]. Since a sequence identity of 92% was reported between the human and feline her2 [12,13], the use of monoclonal antibodies (mAbs) in the feline mammary carcinoma could be an alternative and attractive therapeutic approach
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
