NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia

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Scopim-Ribeiro, Renata ^{[1, 2]} ; Machado-Neto, Joao Agostinho ^{[3, 2]} ; Eide, Christopher A. ^{[1, 4]} ; Coelho-Silva, Juan Luiz ^[2] ; Fenerich, Bruna Alves ^[2] ; Fernandes, Jaqueline Cristina ^[2] ; Scheucher, Priscila Santos ^[2] ; Stevens, Samantha L. Savage ^[1] ; Campos, Paula de Melo ^[5] ; Olalla Saad, Sara T. ^[5] ; Palma, Leonardo de Carvalho ^[2] ; de Figueiredo-Pontes, Lorena Lobo ^[2] ; Simoes, Belinda Pinto ^[2] ; Rego, Eduardo Magalhaes ^{[2, 6]} ; Tognon, Cristina E. ^{[1, 4]} ; Druker, Brian J. ^{[1, 4]} ; Traina, Fabiola ^[2]

Afiliação do(s) autor(es)

^[1] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 - USA

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Med Imaging Hematol & Oncol, Av Bandeirante 3900, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

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

^[5] Univ Estadual Campinas, Hematol & Transfus Med Ctr, Hemoctr, UNICAMP, Campinas, SP - Brazil

^[6] Univ Sao Paulo, Fac Med, Hematol Div, LIM31, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INVESTIGATIONAL NEW DRUGS; v. 39, n. 3 JAN 2021.
• Citações Web of Science: 0

Resumo

Chronic myeloid leukemia (CML) is successfully treated with BCR-ABL1 tyrosine kinase inhibitors, but a significant percentage of patients develop resistance. Insulin receptor substrate 1 (IRS1) has been shown to constitutively associate with BCR-ABL1, and IRS1-specific silencing leads to antineoplastic effects in CML cell lines. Here, we characterized the efficacy of NT157, a pharmacological inhibitor of IGF1R-IRS1/2, in CML cells and observed significantly reduced cell viability and proliferation, accompanied by induction of apoptosis. In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1(T315I) mutant, NT157 inhibited BCR-ABL1, IGF1R, IRS1/2, PI3K/AKT/mTOR, and STAT3/5 signaling, increased CDKN1A, FOS and JUN tumor suppressor gene expression, and reduced MYC and BCL2 oncogenes. NT157 significantly reduced colony formation of human primary CML cells with minimal effect on normal hematopoietic cells. Exposure of primary CML cells harboring BCR-ABL1(T315I) to NT157 resulted in increased apoptosis, reduced cell proliferation and decreased phospho-CRKL levels. In conclusion, NT157 has antineoplastic effects on BCR-ABL1 leukemogenesis, independent of T315I mutational status. (AU)

• Processo FAPESP: 14/06037-6 - Investigação do efeito do silenciamento do IRS1/IRS2 no fenótipo de células hematopoiéticas primárias normais CD34+ e leucêmicas Bcr-Abl+
• Beneficiário: Renata Scopim Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/01639-3 - Investigacao da inibicao de IRS1/IRS2 em celulas BCR-ABL1 positivas utilizando modelo murino
• Beneficiário: Renata Scopim Ribeiro
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado