Anti-Leukemic Properties of the Kinase Inhibitor OTSSP167 in T Cell Acute Lymphoblastic Leukemia

The remission rates of T-cell acute lymphoblastic leukemia (T-ALL), a hematological malignancy in children, have improved through the years. Despite this advance, 10-20% of the patients do not respond to current therapy, and relapse leukemia is the leading cause of death in children with cancer. Our previous work showed aberrant activation of the actionable MAP2K7-JNK pathway in pediatric T-ALL and proposed this pathway as a target for pharmacological inhibition. Here we demonstrate the anti-leukemic capacity of the kinase inhibitor OTSSP167 in T-ALL via MAP2K7 inhibition. OTSSP167, a MELK inhibitor shown to also inhibit MAP2K7, showed a dose-dependent cytotoxicity in a panel of T-ALL cell lines with IC50 in the nanomolar range (10-50 nM). OTSSP167 induced apoptosis and G2/M cell cycle arrest that correlated with increased cleavage of PARP and caspase 3 and elevated levels of cyclin B1 and phosphorylated CDC2. Immunoblot blot analysis shows OTSSP167 treatment inhibited the MAP2K7-JNK-ATF2 pathway, in addition to MELK, in a panel of T-ALL cell lines. Biochemical kinase assay shows inhibition of MAP2K7 kinase activity with an IC50 of 160 nM. Furthermore, OTSSP167 was able to inhibit MAP2K7 activated by treatment of T-ALL cells with sorbitol. This kinase inhibitor shows low toxicity in mice (10 mg/Kg) and controls leukemia burden in cell-based xenograft model with significant reduction on the expansion of KOPT-K1 cells and improved survival (P=0.003). Furthermore, OTSSP167 was able to control leukemia in patient-derived xenograft (PDX) model and to target leukemia-initiating cells in the NOTCH1-induced T-ALL mouse model. Altogether, OTSSP167 is a potent MAP2K7 inhibitor with low toxicity that emerges as a potential adjuvant drug to increase treatment response and reduce relapses in pediatric T-ALL.