Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2(V617F) driven cells

Autor(es)

Fernandes, Jaqueline Cristina ; Fenerich, Bruna Alves ; Alves-Silva, Antonio Bruno ; Fonseca, Natasha Peixoto ; Coelho-Silva, Juan Luiz ; Scheucher, Priscila Santos ; Rego, Eduardo Magalhaes ; Figueiredo-Pontes, Lorena Lobo ; Machado-Neto, Joao Agostinho ; Traina, Fabiola

• Tipo de documento: Artigo Científico
• Fonte: TOXICOLOGY IN VITRO; v. 83, p. 7-pg., 2022-05-26.

Resumo

Myeloproliferative neoplasms (MPN) belong to a group of clonal diseases of hematopoietic stem cells characterized by aberrant proliferation of mature myeloid lineages. The constitutive activation of the JAK2/STAT signaling pathway is now well established to play a central role in MPN pathogenesis; however, accumulating evidence now indicates that the IGF1R-mediated signaling pathway contributes to the maintenance of the malignant phenotype. Studies using inhibitors of IGF1-mediated signaling have reported cytotoxic effects in cellular and murine models of MPN, but no consensus has been reached regarding the potency and efficacy of inhibitors of the IGF1R-related pathway in this context. In the present study, we compared the potency and efficacy of three inhibitors of IGF1R-related pathways in a JAK2(V617F)-driven cellular model. These inhibitors (NT157, OSI-906, and NVP-AEW54) present antineoplastic activity with similar efficacy in Ba/F3 JAK2(V617F) cells, with NT157 showing the greatest potency. Both the induction of apoptosis and reduction in cell proliferation were associated with the observed reduction in cell viability. Downregulation of JAK2/STAT signaling was an advantageous off-target effect of all three inhibitors. These preclinical studies reinforce the potential of the IGF1R-related pathway as a therapeutic target in MPN. (AU)

• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/19864-6 - Investigação da participação das proteínas IRS1 e IRS2 na hematopoese normal e síndrome mielodisplásica utilizando modelos murinos e células-tronco hematopoéticas humanas
• Beneficiário: Fabíola Traina
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/02200-2 - Investigação funcional da participação de IRS2 em neoplasias mieloproliferativas crônicas BCR-ABL1 negativas
• Beneficiário: Fabíola Traina
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/14049-0 - Investigação de mutações na via IGF1R/IRS em Neoplasia Mieloproliferativa e o efeito de inibidores farmacológicos desta via de sinalização em modelo murino knockin para a mutação JAK2V617F
• Beneficiário: Jaqueline Cristina Fernandes
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular