NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2(V617F)-positive myeloproliferative neoplasm cells

Author(s):Show less -

Fenerich, Bruna Alves ^{[1, 2]} ; Fernandes, Jaqueline Cristina ^{[1, 2]} ; Rodrigues Alves, Ana Paula Nunes ^{[1, 2]} ; Coelho-Silva, Juan Luiz ^{[1, 2]} ; Scopim-Ribeiro, Renata ^{[1, 2]} ; Scheucher, Priscila Santos ^[1] ; Eide, Christopher A. ^{[3, 4]} ; Tognon, Cristina E. ^{[3, 4]} ; Druker, Brian J. ^{[3, 4]} ; Rego, Eduardo Magalhaes ^{[5, 1, 2]} ; Machado-Neto, Joao Agostinho ^{[6, 1]} ; Traina, Fabiola ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Med Images Hematol & Clin Oncol, Ribeirao Preto, SP - Brazil

^[2] Sao Paulo Res Fdn, Ctr Cell Based Therapy, Ribeirao Preto, SP - Brazil

^[3] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 - USA

^[4] Howard Hughes Med Inst, Portland, OR - USA

^[5] Univ Sao Paulo, Sch Med, Dept Internal Med, Sao Paulo - Brazil

^[6] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: SIGNAL TRANSDUCTION AND TARGETED THERAPY; v. 5, n. 1 JAN 24 2020.
• Web of Science Citations: 9

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 JAK2(V617F), 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 JAK2(V617F)-positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2(V617F) cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G(2)/M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NF kappa B 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. (AU)

• FAPESP's process: 15/09324-9 - Investigation of the effect of combined treatment with pharmacological inhibitors of JAK2 and IRS2 or mTOR in JAK2 V617F cells
• Grantee: Bruna Alves Fenerich
• Support Opportunities: Scholarships in Brazil - Master
• 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: 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: 14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Projects - Thematic Grants