Anti-leukemic properties of the kinase inhibitor OTSSP167 in T cell acute lymphoblastic leukemia.

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, we here demonstrate that OTSSP167, recently shown to inhibit MAP2K7, has anti-leukemic 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 inhibition of MAP2K7 kinase activity and lower activation of its downstream substrate, JNK. Other leukemic T cell survival pathways were also inhibited, such as mTOR and NOTCH1. 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 blood, bone marrow, and the spleen of three 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 anti-leukemic 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.