TY - JOUR
T1 - NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia
AU - Scopim-Ribeiro, Renata
AU - Machado-Neto, João Agostinho
AU - Eide, Christopher A.
AU - Coelho-Silva, Juan Luiz
AU - Fenerich, Bruna Alves
AU - Fernandes, Jaqueline Cristina
AU - Scheucher, Priscila Santos
AU - Savage Stevens, Samantha L.
AU - de Melo Campos, Paula
AU - Olalla Saad, Sara T.
AU - de Carvalho Palma, Leonardo
AU - de Figueiredo-Pontes, Lorena Lobo
AU - Simões, Belinda Pinto
AU - Rego, Eduardo Magalhães
AU - Tognon, Cristina E.
AU - Druker, Brian J.
AU - Traina, Fabiola
N1 - Publisher Copyright:
© 2021, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - BCR-ABL1
KW - Insulin receptor substrate 1
KW - Leukemogenesis
KW - NT157
UR - http://www.scopus.com/inward/record.url?scp=85098727034&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098727034&partnerID=8YFLogxK
U2 - 10.1007/s10637-020-01028-8
DO - 10.1007/s10637-020-01028-8
M3 - Article
C2 - 33403501
AN - SCOPUS:85098727034
SN - 0167-6997
VL - 39
SP - 736
EP - 746
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 3
ER -