Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia.

摘要: Polo-like kinases (PLKs) and Aurora (AKs) act as key cell cycle regulators in healthy human cells. In cancer, these protein are often overexpressed dysregulated, thus contributing to uncontrolled proliferation growth. T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy arising the thymus from progenitors. Primary chemoresistant relapsed T-ALL patients have yet poor outcome, therefore novel therapies, targeting signaling pathways important for leukemic proliferation, required. Here, we demonstrate potential therapeutic effects of BI6727, MK-5108, GSK1070916, three selective inhibitors PLK1, AK-A, AK-B/C, respectively, panel lines primary cells patients. The drugs were both cytostatic cytotoxic by inducing G2/M-phase arrest apoptosis. retained part their pro-apoptotic activity presence MS-5 bone marrow stromal Moreover, document first time that BI6727 perturbed PI3K/Akt/mTORC2 MEK/ERK/mTORC1 pathways, combination with specific aforementioned (MK-2206, CCI-779) displayed significantly synergistic effects. Taken together, our findings indicate PLK1 AK display being employed innovative strategies improving patient outcome.