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

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Summary

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.

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Acknowledgements

The authors would like to thank Dr Nicola Conran for English revision.

Funding

This study was financed in part by São Paulo Research Foundation (FAPESP), Grants #14/06037-6, #16/01639-3, #14/50947-7, #13/08135-2; in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES); and in part by National Counsel of Technological and Scientific Development (CNPq), Grants #460750/2014-3, #305158/2013-9.

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Authors and Affiliations

  1. Department of Medical Imaging, Hematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirante 3900, Ribeirão Preto, São Paulo, Brazil

    Renata Scopim-Ribeiro, João Agostinho Machado-Neto, Juan Luiz Coelho-Silva, Bruna Alves Fenerich, Jaqueline Cristina Fernandes, Priscila Santos Scheucher, Leonardo de Carvalho Palma, Lorena Lobo de Figueiredo-Pontes, Belinda Pinto Simões, Eduardo Magalhães Rego & Fabiola Traina

  2. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Renata Scopim-Ribeiro, Christopher A. Eide, Samantha L. Savage Stevens, Cristina E. Tognon & Brian J. Druker

  3. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    João Agostinho Machado-Neto

  4. Howard Hughes Medical Institute, Portland, OR, USA

    Christopher A. Eide, Cristina E. Tognon & Brian J. Druker

  5. Hematology and Transfusion Medicine Center, University of Campinas/Hemocentro UNICAMP, Campinas, São Paulo, Brazil

    Paula de Melo Campos & Sara T. Olalla Saad

  6. Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil

    Eduardo Magalhães Rego

Authors
  1. Renata Scopim-Ribeiro
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  2. João Agostinho Machado-Neto
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Contributions

R.S-R designed, executed and analyzed the experiments and prepared the manuscript. J.A.M-N., J.L.C-S. participated in experiments and analyzed, and prepared the manuscript. B.A.F., J.C.F. provided inputs and participated in experiments using cell lines and primary human cells. P.S.S. participated in flow cytometry experiments and data analysis. C.A.E., S.L.S.S., C.E.T., B.J.D. provided inputs and participated in the interpretation of manuscript data. P.M.C., S.T.O.S., L.C.P., L.L.F-P., B.P.S, E.M.R. contributed to recruiting patients and collecting data. F.T. supervised and participated in overall design of study, experiments and analyses. All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Fabiola Traina.

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Conflict of interest

Brian J. Druker potential competing interests- SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI BioPharma (inactive); Scientific Founder & Stock: MolecularMD; Board of Directors & Stock: Amgen; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Clinical Trial Funding: Novartis, Bristol-Myers Squibb, Pfizer; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license). Renata Scopim-Ribeiro declares that she has no conflict of interest. João Agostinho Machado-Neto declares that he has no conflict of interest. Christopher A. Eide declares that he has no conflict of interest. Juan Luiz Coelho-Silva declares that he has no conflict of interest. Bruna Alves Fenerich declares that she has no conflict of interest. Jaqueline Cristina Fernandes declares that she has no conflict of interest. Priscila Santos Scheucher declares that she has no conflict of interest. Samantha L. Savage Stevens declares that she has no conflict of interest. Paula de Melo Campos declares that she has no conflict of interest. Sara T. Olalla Saad declares that she has no conflict of interest. Leonardo de Carvalho Palma declares that he has no conflict of interest. Lorena Lobo de Figueiredo-Pontes declares that she has no conflict of interest. Belinda Pinto Simões declares that she has no conflict of interest. Eduardo Magalhães Rego declares that he has no conflict of interest. Cristina E. Tognon declares that she has no conflict of interest. Fabiola Traina declares that she has no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and its later amendments.

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Informed consent was obtained from all individual participants included in the study.

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Scopim-Ribeiro, R., Machado-Neto, J.A., Eide, C.A. et al. NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia. Invest New Drugs 39, 736–746 (2021). https://doi.org/10.1007/s10637-020-01028-8

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