IGF1R/IRS1 targeting has cytotoxic activity and inhibits PI3K/AKT/mTOR and MAPK signaling in acute lymphoblastic leukemia cells

Author(s)

Nunes Rodrigues Alves, Ana Paula ^[1] ; Fernandes, Jaqueline Cristina ^[1] ; Fenerich, Bruna Alves ^[1] ; Coelho-Silva, Juan Luiz ^[1] ; Scheucher, Priscila Santos ^[1] ; Simoes, Belinda Pinto ^[1] ; Rego, Eduardo Magalhaes ^[1] ; Ridley, Anne J. ^{[2, 3]} ; Machado-Neto, Joao Agostinho ^{[4, 1]} ; Traina, Fabiola ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Internal Med, Ribeirao Preto Med Sch, Av Bandeirante 3900, Ribeirao Preto, SP - Brazil

^[2] Kings Coll London, Randall Ctr Cell & Mol Biophys, London - England

^[3] Univ Bristol, Sch Cellular & Mol Med, Bristol, Avon - England

^[4] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

• Document type: Journal article
• Source: Cancer Letters; v. 456, p. 59-68, 2019.
• Web of Science Citations: 3

Abstract

The IGF1R/IRS1 signaling is activated in acute lymphoblastic leukemia (ALL) and can be targeted by the pharmacological inhibitors NT157 (IGF1R-IRS1/2 inhibitor) and OSI-906 (IGF1R/IR inhibitor). Here we investigate the cellular and molecular effects of NT157 and OSI-906 in ALL cells. NT157 and OSI-906 treatment reduced viability, proliferation and cell cycle progression in ALL cell lines. Similarly, in primary samples of patients with ALL, both OSI-906 and NT157 reduced viability, but only NT157 induced apoptosis. NT157 and OSI-906 did not show cytotoxicity in primary samples from healthy donor. NT157 and OSI-906 significantly decreased Jurkat cell migration, but did not modulate Namalwa migration. Consistent with the more potent effect of NT157 on cells, NT157 significantly modulated expression of 25 genes related to the MAPK signaling pathway in Jurkat cells, including oncogenes and tumor suppressor genes. Both compounds inhibited mTOR and p70S6K activity, but only NT157 inhibited AKT and 4-EBP1 activation. In summary, in ALL cells, NT157 has cytotoxic activity, whereas OSI-906 is cytostatic. NT157 has a stronger effect on ALL cells, and thus the direct inhibition of IRS1 may be a potential therapeutic target in ALL. (AU)

• FAPESP's process: 14/14844-9 - Functional Investigation of IGF1/IRS1 signaling pathway in acute lymphoblastic leukemia
• Grantee: Ana Paula Nunes Rodrigues Alves
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/50947-7 - INCT 2014: in Stem Cell and Cell Therapy
• Grantee: Dimas Tadeu Covas
• Support Opportunities: Research Projects - Thematic 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