| Full text | |
| Author(s): Show less - |
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]
Total Authors: 17
|
| Affiliation: | [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
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | INVESTIGATIONAL NEW DRUGS; v. 39, n. 3 JAN 2021. |
| Web of Science Citations: | 0 |
| 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. (AU) | |
| FAPESP's process: | 14/06037-6 - Investigation of IRS1/IRS2 silencing effects on the phenotype of CD34+ normal primary hematopoietic cells and BCR-ABL+ leukemic cells |
| Grantee: | Renata Scopim Ribeiro |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| 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 |
| FAPESP's process: | 16/01639-3 - Investigation of IRS1/IRS2 inhibition in BCR-ABL1 cells using murine models |
| Grantee: | Renata Scopim Ribeiro |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |