A canine case of malignant melanoma carrying a KIT c.1725_1733del mutation treated with toceranib: a case report and in vitro analysis

Abstract

Background Canine malignant melanoma is highly aggressive and generally chemoresistant. Toceranib is a kinase inhibitor drug that inhibits several tyrosine kinases including the proto-oncogene receptor tyrosine kinase KIT. Although canine malignant melanoma cells often express KIT, a therapeutic effect for toceranib has yet to be reported for this tumor, with only a small number of patients studied to date. This is a case report of a dog with malignant melanoma that experienced a transient response to toceranib. Furthermore, the KIT expressed in the tumor of this case was examined using molecular analysis. Case presentation A Shiba Inu dog presented with a gingival malignant melanoma extending into surrounding structures with metastasis to a submandibular lymph node. The dog was treated with toceranib (Palladia®; 2.6–2.9 mg/kg, orally, every other day) alone. Improvement of tumor-associated clinical signs (e.g., halitosis, tumor hemorrhage, trismus, and facial edema) with reduced size of the metastatic lymph node was observed on Day 15. The gingival tumor and associated masses in the masseter and pterygoid muscles decreased in size by Day 29 of treatment. Toceranib treatment was terminated on Day 43 due to disease progression and the dog died on Day 54. The tumor of this dog had a novel deletion mutation c.1725_1733del within KIT and the mutation caused ligand-independent phosphorylation of KIT, which was suppressed by toceranib. This mutation was considered to be an oncogenic driver mutation in the tumor of this dog, thereby explaining the anti-tumor activity of toceranib. Conclusions This is the first report that presents a canine case of malignant melanoma that responded to toceranib therapy. KIT encoded by KIT harboring a mutation c.1725_1733del is a potential therapeutic target for toceranib in canine malignant melanoma. Further investigation of the KIT mutation status and toceranib therapy in canine malignant melanoma will need to be undertaken.

Diagnosis and histopathologic prognostication of canine melanocytic neoplasms: A consensus of the Oncology‐Pathology Working Group

“…Both of the above studies concluded that there are no current documented indications, in regards to c‐Kit mutation status or KIT labelling, to suggest tyrosine kinase inhibitors (TKIs) would be beneficial for these tumours 14,44 . However, a recent single case report described a dog with a gingival MM that had a novel deletion mutation c.1725_1733del within KIT, which was considered to be an oncogenic driver mutation 45 …”

“…14,44 However, a recent single case report described a dog with a gingival MM that had a novel deletion mutation c.1725_1733del within KIT, which was considered to be an oncogenic driver mutation. 45 Other oral melanocytic neoplasm studies that were reviewed could not demonstrate prognostic utility for the markers that they evaluated, may have found promising statistical significance but were too preliminary to make any significant conclusions, were not designed as prognostic studies, or only used melanoma cell lines. [5][6][7]11,13,15,17,19,21,22,38,43,47,49 These markers included: a metabolite profile that included citric acid, 3,5,6,11,13,15,17,19,21,22,38,43,47,49 3.3 | Recommendations for prognostication Tables 3 and 4 can be used as guides for prognostication.…”

Multimodal Treatment of a Canine Lingual Melanoma Using a Combination of Immunotherapy and a Tyrosine Kinase Inhibitors

“…Masitinib has previously been reported to be of very variable efficacy in treatment of oral melanomas and was deemed not an appropriate sole-agent option for treatment of advanced malignant melanoma in a cohort of dogs [9]. Treatment of canine oral melanoma with toceranib may offer benefits due its wider range of molecular targets, and has been previously reported to have some efficacy in a single case of advanced metastatic oral melanoma, however survival time was only 54 days [39].…”

A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

“…Copy number increases in Kit have been reported in 26-65% of COMs, either as focal amplifications or part of large chromosomal rearrangements [3,45,60], but these do not necessarily result in increased expression at a protein level [60], and there is no significant correlation between KIT expression and any histopathologic feature, WHO stage, or overall patient survival times [61,62]. A recent clinical trial of TKI masitinib mesylate in 17 patients with advanced COM yielded disappointing results [63], and further trials are required to assess TKI use as adjunctive treatments, particularly for the individual cases where activating mutations are present [3,59,64].…”