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Title: NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia
Authors: SCOPIM-RIBEIRO, RenataMACHADO-NETO, Joao AgostinhoEIDE, Christopher A.COELHO-SILVA, Juan LuizFENERICH, Bruna AlvesFERNANDES, Jaqueline CristinaSCHEUCHER, Priscila SantosSTEVENS, Samantha L. SavageCAMPOS, Paula de MeloSAAD, Sara T. OlallaPALMA, Leonardo de CarvalhoFIGUEIREDO-PONTES, Lorena Lobo deSIMOES, Belinda PintoREGO, Eduardo MagalhaesTOGNON, Cristina E.DRUKER, Brian J.TRAINA, Fabiola
Citation: INVESTIGATIONAL NEW DRUGS, v.39, n.3, p.736-746, 2021
Abstract: 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.
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Artigos e Materiais de Revistas Científicas - FM/MCM
Departamento de Clínica Médica - FM/MCM

Artigos e Materiais de Revistas Científicas - LIM/31
LIM/31 - Laboratório de Genética e Hematologia Molecular

Artigos e Materiais de Revistas Científicas - ODS/03
ODS/03 - Saúde e bem-estar

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