NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells

Bruna Alves Fenerich, Jaqueline Cristina Fernandes, Ana Paula Nunes Rodrigues Alves, Juan Luiz Coelho-Silva, Renata Scopim-Ribeiro, Priscila Santos Scheucher, Christopher A. Eide, Cristina E. Tognon, Brian J. Druker, Eduardo Magalhães Rego, João Agostinho Machado-Neto, Fabiola Traina

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2V617F, and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2V617F-positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G2/M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, and JUN) (p < 0.05). NT157 induced genotoxic stress in a JAK2/STAT-independent manner. NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients (p < 0.05). These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

Original languageEnglish (US)
Article number5
JournalSignal Transduction and Targeted Therapy
Volume5
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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