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

Author(s)

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

• Document type: Journal article
• Source: TOXICOLOGY IN VITRO; v. 83, p. 7-pg., 2022-05-26.

Abstract

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)

• FAPESP's process: 13/08135-2 - CTC - Center for Cell-Based Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/19864-6 - Investigation of IRS1 and IRS2 function in normal hematopoiesis and myelodysplastic syndrome using murine models and human hematopoietic stem cells
• Grantee: Fabíola Traina
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/02200-2 - Functional investigation of IRS2 in BCR-ABL1 negative chronic myeloproliferative neoplasms
• Grantee: Fabíola Traina
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/14049-0 - Investigation of mutations in IGF1R/IRS pathway in Myeloproliferative Neoplasm and the effect of pharmacological inhibitors of this signaling pathway in JAK2V617F knockin murine model
• Grantee: Jaqueline Cristina Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants