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The pharmacological IGF1R-IRS1/2 inhibitor NT157 presents multiple anti-neoplastic effects in myeloproliferative neoplasms

2017; Elsevier BV; Volume: 130; Linguagem: Inglês

10.1182/blood.v130.suppl_1.1253.1253

1528-0020

Bruna Alves Fenerich, João Agostinho Machado‐Neto, Ana Paula Nunes Rodrigues Alves, Paula de Melo Campos, Jaqueline Cristina Fernandes, Juan Luiz Coelho‐Silva, Renata Scopim Ribeiro, Fernanda B da Silva, Priscila Santos Scheucher, Lorena Lôbo Figueiredo-Pontes, Eduardo Magalhães Rego, Fabı́ola Traina,

Cytokine Signaling Pathways and Interactions

Abstract Introduction: The recurrent V617F mutation in JAK2 plays an important role in the pathogenesis of BCR-ABL1 negative myeloproliferative neoplasms (MPN). Absence of complete clinical response to ruxolitinib, a JAK1/2 inhibitor, highlights the need to target other signaling pathways that contribute to JAK2. Recent evidence indicates that the IGF1R/IRS pathway is a potential target in MPN: (i) insulin receptor substrate 2 (IRS2) cooperates with malignant transformation induced by JAK2V617F, and (ii) increased IGF1 signaling induced by AIRAPL down-regulation causes MPN in mice. NT157 is a synthetic compound designed as an IRS1/2 inhibitor, which presented anti-neoplastic effects in solid tumors. Aims: The objective herein was tocharacterize the molecular and cellular effects of NT157 treatment, combined or not with ruxolitinib, in MPN JAK2V617F. Methods: HEL and SET2 cell lines (both carrying JAK2V617F mutation) were treated or not with vehicle, NT157 and/or ruxolitinib and submitted to evaluation of cell viability (MTT assay), apoptosis (annexin V/PI and caspase cleavage), proliferation (Ki-67), clonogenicity (colony forming assay), cell cycle (PI), gene expression (PCR array and qPCR) and protein expression/activation (Western blot). Primary cells from polycythemia vera (PV) patients (n=3) were exposed to NT157 (3.2 µM) treatment and evaluated for erythropoietin-independent colony formation. Statistical analysis was performed using ANOVA or Student's t test. P -value Disclosures No relevant conflicts of interest to declare.