While intensive chemotherapy regimens result in remission in approximately 80% of pediatric and 45% of adult ALL patients, new approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Early T-cell precursor (ETP) ALL, a subset of T-ALL associated with a higher rate of relapse and induction failure, with a 10-year overall survival of 19% as compared with 84% for all other T-ALLs. PIM protein kinases are overexpressed in a number of hematopoietic malignancies, including ALL, with its overexpression being associated with poor prognosis. Pan-PIM inhibitors (PIMi) are being tested in clinical trials in patients with relapsed/refractory multiple myeloma and acute myeloid leukemia. Analysis of the effects of PIMi (AZD1208/LGB321) on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Immunophenotype of all the PIMi insensitive cells lines was consistent with a more mature T-ALL phenotype. In contrast, sensitive cells, had an immature or ETP-ALL phenotype.
Bioinformatics analysis of three independent T-ALL patient datasets (GSE28703, E-MEXP-313, and GSE62156) demonstrated overexpression of PIM1 in the majority of ETP-ALLs and in a small subset of non-ETP-ALL. We also identified 58 genes changing significantly between PIMi sensitive versus insensitive cell lines that were common to the differential genes between ETP versus non-ETP ALL cases from GSE28703, suggesting that high PIM1 expression along with 58 gene signature could be a driver of the ETP phenotype.
Importantly, we have made the novel observation that, combination of Ponatinib, a tyrosine kinase inhibitor (TKI) with the PIMi is synergistically lethal to T-ALL cells with ETP phenotype. These agents appear to work together by inducing PARP and Caspase cleavage, sufficient to drive apoptosis. Following engraftment of NSG mice with H-SB2-Luc cells, three weeks of dual therapy with AZD1208 (30mg/kg/day) and Ponatinib (3mg/kg/day) significantly abrogated leukemia as evidenced by optical scanning for luciferase cells, and reduced number of hCD45+ leukemic cells in the peripheral blood and bone marrow. Also, the dual therapy significantly prolonged the survival of the treated mice. In summary, our work demonstrates a strong preclinical rationale for a novel treatment strategy of combining PIMi and TKI to treat T-ALL patients with high PIM expression.
Citation Format: Sathish Kumar Reddy Padi, Libia Luevano, Neha Singh, Jiin Song, Ritu Pandey, Jon C. Aster, Xue-Zhong Yu, Shikhar Mehrotra, Andrew Kraft. Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5820. doi:10.1158/1538-7445.AM2017-5820