Inhibiting PIM2 sensitizes CML to Gleevec

INDICATION: Chronic myelogenous leukemia (CML)

Patient sample, cell culture and mouse studies suggest inhibiting PIM2 could sensitize CML to the dual BCR-ABL/c-Kit inhibitor Gleevec imatinib. In CML patients, levels of PIM2 mRNA were higher in CML stem cells, which are resistant to Gleevec, than in hematopoietic stem cells (HSCs). In patient-derived CML stem cells, two shRNAs targeting PIM2, a pan-PIM kinase inhibitor tool compound or the pan-PIM kinase inhibitor PIM447 increased sensitivity to Gleevec compared with a non-targeting shRNA or vehicle. In the CML stem cells, patient-derived HSCs and two Gleevec-resistant human CML cell lines, the pan-PIM kinase inhibitor tool compound plus Gleevec decreased proliferation compared with either agent alone. In a mouse model of CML, the combination increased survival and decreased leukemic burden in the peripheral blood. In a patient-derived xenograft (PDX) mouse model of CML, the combination decreased leukemic burden in the peripheral blood and spleen. Next steps could include testing selective PIM2 inhibitors in the models...