Molecular characterization of canine SHP2 mutants and anti‐tumour effect of SHP2 inhibitor, SHP099 , in a xenograft mouse model of canine histiocytic sarcoma
| Autor: | Masaki Michishita, Ryo Miyamoto, Kyoichi Tamura, Tomokazu Nagashima, Hiroyuki Tani, Makoto Bonkobara |
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| Rok vydání: | 2021 |
| Předmět: |
Mutant
Phosphatase medicine.disease_cause law.invention Rodent Diseases Mice Dogs Piperidines law In vivo Neoplasms Canine Histiocytic Sarcoma medicine Animals Dog Diseases Mutation General Veterinary Chemistry Molecular biology Disease Models Animal Pyrimidines Cell culture Recombinant DNA Heterografts Histiocytic Sarcoma Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Veterinary and Comparative Oncology. 20:109-117 |
| ISSN: | 1476-5829 1476-5810 |
| Popis: | Canine histiocytic sarcoma (HS) is an aggressive and highly metastatic neoplasm. Mutations in src homology 2 domain-containing phosphatase 2 (SHP2; encoded by PTPN11), which recently have been identified in canine HS tumour cells, could be attractive therapeutic targets for SHP099, an allosteric inhibitor of SHP2. Here, molecular characteristics of wild-type SHP2 and four SHP2 mutants (p.Ala72Gly, p.Glu76Gln, p.Glu76Ala and p.Gly503Val), including one that was newly identified in the present study, were investigated. Furthermore, in vivo effects of SHP099 on a HS cell line carrying SHP2 p.Glu76Ala were examined using a xenograft mouse model. While SHP2 Glu76 mutant cell lines and SHP2 wild-type/Gly503 mutant cell lines are highly susceptible and non-susceptible to SHP099, respectively, a cell line carrying the newly identified SHP2 p.Ala72Gly mutation exhibited moderate susceptibility to SHP099. Among recombinant wild-type protein and four mutant SHP2 proteins, three mutants (SHP2 p.Ala72Gly, p.Glu76Gln, p.Glu76Ala) were constitutively activated, while no activity was detected in wild-type SHP2 and SHP2 p.Gly503Val. Activities of these constitutively activated proteins were suppressed by SHP099; in particular, Glu76 mutants were highly sensitive. In the xenograft mouse model, SHP099 showed anti-tumour activity against a SHP2 p.Glu76Ala mutant cell line. Thus, there was heterogeneity in molecular characteristics among SHP2 mutants. SHP2 p.Glu76Ala and perhaps p.Glu76Gln, but not wild-type SHP2 or SHP2 p.Gly503Val, were considered to be oncogenic drivers targetable with SHP099 in canine HS. Further studies will be needed to elucidate the potential of SHP2 p.Ala72Gly as a therapeutic target of SHP099 in canine HS. |
| Databáze: | OpenAIRE |
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