Increased Expression Of The Chemoresistance Markers P-Glycoprotein (Pgp) And Breast Cancer Resistance Protein (Bcrp) In A Canine Cutaneous Mast Cell Tumor Treated With Chemotherapy And Tyrosine Kinase Inhibitor

The onset of multidrug resistance can be related to PGP and BCRP expression, already described in canine neoplasia (2,3). Medical therapeutic approach for canine mast cell tumors (MCT) includes conventional chemotherapy and tyrosine kinase inhibitors (TKIs). TKIs are able to block disregulated KIT activity (1), whose immunohistochemical (IHC) pattern has been related to the biological behaviour of MCT (4). A case of a non-responsive to treatment MCT is described below and IHC expression of PGP, BCRP and KIT were examined, before and after treatment. A 7 years old, female spayed, mixed-breed, dog was referred for a cutaneous carpal mass and ipsilateral prescapular lymphadenomegaly. Lesions were removed and the final diagnosis was cutaneous MCT (Patnaik’s Grade 2, Kiupel’s low grade) with lymphnode metastases. The owner refused adjuvant chemotherapy and 6 months later, 3 new mast cell tumors in the surgical scar region were diagnosed. A Vinblastine + Prednisone protocol was initiated. After three doses, the disease progressed and tumors were excised: final histologic diagnosis was cutaneous MCT (Patnaik’s Grade 2, Kiupel’s high grade), infiltrating subcutaneous MCT and MCT lymphnode metastasis. Masitinib, a TKIs, was added to the chemotherapeutic protocol. After 2 months, the dog developed new MCTs and a rescue protocol with Lomustine was initiated. Due to the disease progression, the dog was euthanized 285 days after diagnosis. A retrospective IHC exam with PGP, BCRP, KIT was performed and evaluated with already described methods (4,5,6). Samples collected before chemotherapy did not show PGP (0%cell/HPF) and BCRP (<10%cell/HPF) expression; KIT’s staining expression was pattern I in the cutaneous mass, and pattern III in the node metastasis. After chemotherapy, an increased expression of PGP from null to low (<10%cell/HPF) in the cutaneous metastasis, and from null to intermediate (10-50% cell/HPF) in the subcutaneous and nodal metastasis were detected; BCRP expression was positive in all the samples (>10%cell/HPF); KIT staining was pattern III (diffuse cytoplasmic) in all the samples. The increase in PGP expression, seen in MCT after the first treatment, is likely to be related with the onset of PGP-mediated chemoresistance, being Vinblastine a substrate of PGP (5). These chemotherapeutic drugs, instead, are not BCRP substrates (7), however, the BCRP expression has been associated with biological aggressiveness (7), present in this case. Pattern III of KIT, seen in all metastases, is related to worse prognosis (4). The increased expression of PGP, BCRP and KIT in this case could be related to a chemoresistant and malignant neoplastic phenotype. 1) Hahn, Drug Update: Masitinib. In: Bonagura & Twedt, Elsevier, Kirk’s Current Veterinary Therapy XV, 360-362; 2014. 2) Ginn et al., Vet Path 33(5):533-41; 1996. 3) Nowak et al., In vivo 23:705-710; 2009. 4) Kiupel et al., Vet Path 41:371–377; 2004. 5) Petterino et al., Veterinaria 18(2):35-39; 2004. 6) Diestra et al., J Pathol 198:213–219; 2002. 7) Nakanishi et al., CJC 31(2),73-99; 2012