Language
English
Publication Date
2-14-2023
Journal
Blood Advances
DOI
10.1182/bloodadvances.2022008548
PMID
36399528
PMCID
PMC9979715
PubMedCentral® Posted Date
11-21-2022
PubMedCentral® Full Text Version
Post-print
Abstract
Novel drugs are needed to increase treatment response in children with high-risk T-cell acute lymphoblastic leukemia (T-ALL). Following up on our previous report on the activation of the MAP2K7-JNK pathway in pediatric T-ALL, here we demonstrate that OTSSP167, recently shown to inhibit MAP2K7, has antileukemic capacity in T-ALL. OTSSP167 exhibited dose-dependent cytotoxicity against a panel of T-ALL cell lines with IC50 in the nanomolar range (10-50 nM). OTSSP167 induces apoptosis and cell cycle arrest in T-ALL cell lines, associated at least partially with the inhibition of MAP2K7 kinase activity and lower activation of its downstream substrate, JNK. Other leukemic T-cell survival pathways, such as mTOR and NOTCH1 were also inhibited. Daily intraperitoneal administration of 10 mg/kg OTSSP167 was well tolerated, with mice showing no hematological toxicity, and effective at reducing the expansion of human T-ALL cells in a cell-based xenograft model. The same dosage of OTSSP167 efficiently controlled the leukemia burden in the blood, bone marrow, and spleen of 3 patient-derived xenografts, which resulted in prolonged survival. OTSSP167 exhibited synergistic interactions when combined with dexamethasone, L-asparaginase, vincristine, and etoposide. Our findings reveal novel antileukemic properties of OTSSP167 in T-ALL and support the use of OTSSP167 as an adjuvant drug to increase treatment response and reduce relapses in pediatric T-ALL.
Keywords
Humans, Mice, Animals, Child, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Antineoplastic Agents, Naphthyridines, Protein Kinase Inhibitors, T-Lymphocytes
Published Open-Access
yes
Recommended Citation
Bridges, Cory Seth; Chen, Taylor J; Puppi, Monica; et al., "Antileukemic Properties of the Kinase Inhibitor OTSSP167 in T-Cell Acute Lymphoblastic Leukemia" (2023). Faculty and Staff Publications. 5612.
https://digitalcommons.library.tmc.edu/baylor_docs/5612
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