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

Renata Scopim-Ribeiro, João Agostinho Machado-Neto, Christopher A. Eide, Juan Luiz Coelho-Silva, Bruna Alves Fenerich, Jaqueline Cristina Fernandes, Priscila Santos Scheucher, Samantha L. Savage Stevens, Paula de Melo Campos, Sara T. Olalla Saad, Leonardo de Carvalho Palma, Lorena Lobo de Figueiredo-Pontes, Belinda Pinto Simões, Eduardo Magalhães Rego, Cristina E. Tognon, Brian J. Druker, Fabiola Traina

Research output: Contribution to journalArticlepeer-review

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-ABL1T315I 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-ABL1T315I 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.

Original languageEnglish (US)
Pages (from-to)736-746
Number of pages11
JournalInvestigational New Drugs
Volume39
Issue number3
DOIs
StatePublished - Jun 2021

Keywords

  • BCR-ABL1
  • Insulin receptor substrate 1
  • Leukemogenesis
  • NT157

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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