Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

Tani, Hiroyuki; Kurita, Sena; Miyamoto, Ryo; Ochiai, Kazuhiko; Tamura, Kyoichi; Bonkobara, Makoto

doi:10.1111/vco.12524

Cited by 4 publications

(29 citation statements)

References 23 publications

(39 reference statements)

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“…In the future, this test could be considered in veterinary oncology, to guide treatment procedure toward targeted therapy. Indeed, others and us showed that PTPN11 mutations were associated with the activation of the MAPK pathway, and in vitro test showed that canine HS cell lines were sensitive to MEK inhibitors 27,59,60 . As our ctDNA assay demonstrated a sensitivity of 91.3% and a specificity of 100% for the detection of PTPN11 mutation in the plasma of dogs carrying PTPN11 mutated HS, it could efficiently select dogs susceptible to benefit from this targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, all mutated cases were Bernese mountain dogs. Moreover, we targeted only the two most frequent PTPN11 mutations (E76K and G503V), while some HS cases present other PTPN11 mutations 27,59 . Recently, mutations of KRAS and BRAF were also found in 3 to 7% and less than 1% of canine HS respectively, and were found to be exclusive of PTPN11 mutation 25,27 .…”

Section: Discussionmentioning

confidence: 99%

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Interest of circulating tumor DNA as a biomarker for canine cancers: illustration in histiocytic sarcoma, oral malignant melanoma and multicentric lymphoma

Prouteau

Denis

Fornel³

et al. 2020

Preprint

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Circulating tumor DNA (ctDNA) has become an attractive biomarker in human oncology and may be informative in cancer-affected dogs. By performing ddPCR or PARR methods, we detected tumor-specific point mutations, copy number alterations and chromosomal rearrangements in the plasma of cancer-affected dogs. It allowed the detection of ctDNA in 2/8 (25%) oral malignant melanoma cases, 12/13 (92.3%) lymphoma cases and 21/23 (91.3%) histiocytic sarcoma (HS) cases. The value of ctDNA to diagnose HS was explored in 133 dogs including 49 with HS. In this cohort, screening recurrent PTPN11 mutations in plasma had a specificity of 98.8%, and a sensitivity between 42.8-77% according to HS clinical presentation, being higher in internal forms, especially with pulmonary location. Regarding lymphoma, the follow-up of four dogs showed that the minimal residual disease detection by targeting lymphoma-specific antigen receptor rearrangement in the plasma was concordant with the clinical evaluation. Moreover, ctDNA analysis appeared interesting to assess treatment response and to predict relapse.This study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a relevant biomarker for diagnosis and clinical follow-up. With a growing interest in integrating natural canine tumors to explore new therapies, this biomarker appears promising in comparative oncology research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interest of circulating tumor DNA as a biomarker for canine cancers: illustration in histiocytic sarcoma, oral malignant melanoma and multicentric lymphoma

Prouteau

Denis

Fornel³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…In the future, this test may be considered to guide treatment procedures toward targeted therapy in veterinary oncology practice. Indeed, we and others have shown that PTPN11 mutations are associated with the activation of the MAPK pathway, and in vitro tests have shown that canine HS cell lines are sensitive to MEK inhibitors 27,49,50 . Our ctDNA assay had a sensitivity of 91.3% and a specificity of 100% for the detection of PTPN11 mutations in the plasma of dogs carrying PTPN11-mutated HS, and it could efficiently select dogs that may benefit from this targeted therapy.…”

Section: Discussionmentioning

confidence: 85%

“…In our study, all cases with PTPN11 mutations were found in Bernese mountain dogs. Moreover, we targeted only the two most frequent PTPN11 mutations (E76K and G503V), and some HS cases may have other PTPN11 mutations 27,49 . Recently, mutations in KRAS and BRAF were found in 3-7% and less than 1%, respectively, of canine HS cases and were found to be exclusive to the PTPN11 mutation 25,27 .…”

Section: Discussionmentioning

confidence: 99%

Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma

Prouteau

Denis

Fornel³

et al. 2021

Sci Rep

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Circulating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.

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“…Gly503Val) 11 were examined (Figure 2A). Phosphatase activity was not detectable in wild-type SHP2 or in SHP2 harbouring p.Gly503Val, while constitutive phosphatase activities were observed in SHP2 proteins harbouring p.Ala72Gly, p.Glu76Ala and p.Glu76Gln.…”

Section: Differences In the Levels Of Phosphatase Activity And Sensit...mentioning

confidence: 99%

Molecular characterization of canine SHP2 mutants and anti‐tumour effect of SHP2 inhibitor, SHP099, in a xenograft mouse model of canine histiocytic sarcoma

Tani

Miyamoto

Nagashima

et al. 2021

Vet Comparative Oncology

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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.

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Canine histiocytic sarcoma cell lines with SHP2 p.Glu76Gln or p.Glu76Ala mutations are sensitive to allosteric SHP2 inhibitor SHP099

Cited by 4 publications

References 23 publications

Interest of circulating tumor DNA as a biomarker for canine cancers: illustration in histiocytic sarcoma, oral malignant melanoma and multicentric lymphoma

Interest of circulating tumor DNA as a biomarker for canine cancers: illustration in histiocytic sarcoma, oral malignant melanoma and multicentric lymphoma

Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma

Molecular characterization of canine SHP2 mutants and anti‐tumour effect of SHP2 inhibitor, SHP099, in a xenograft mouse model of canine histiocytic sarcoma

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