title: Therapeutic targeting of Polo-like kinase-1 and Aurora kinases in T-cell acute lymphoblastic leukemia.
abstract: Polo-like kinases (PLKs) and Aurora kinases (AKs) act as key cell cycle regulators in healthy human cells. In cancer, these protein kinases are often overexpressed and dysregulated, thus contributing to uncontrolled cell proliferation and growth. T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy arising in the thymus from T-cell progenitors. Primary chemoresistant and relapsed T-ALL patients have yet a poor outcome, therefore novel therapies, targeting signaling pathways important for leukemic cell proliferation, are required. Here, we demonstrate the potential therapeutic effects of BI6727, MK-5108, and GSK1070916, three selective inhibitors of PLK1, AK-A, and AK-B/C, respectively, in a panel of T-ALL cell lines and primary cells from T-ALL patients. The drugs were both cytostatic and cytotoxic to T-ALL cells by inducing G2/M-phase arrest and apoptosis. The drugs retained part of their pro-apoptotic activity in the presence of MS-5 bone marrow stromal cells. Moreover, we document for the first time that BI6727 perturbed both the PI3K/Akt/mTORC2 and the MEK/ERK/mTORC1 signaling pathways, and that a combination of BI6727 with specific inhibitors of the aforementioned pathways (MK-2206, CCI-779) displayed significantly synergistic cytotoxic effects. Taken together, our findings indicate that PLK1 and AK inhibitors display the potential for being employed in innovative therapeutic strategies for improving T-ALL patient outcome.
authors.affiliation: Department of Biomedical and Neuromotor Sciences; University of Bologna; Bologna, Italy.
authors.forename: Antonino Maria
authors.initials: AM
authors.lastname: Spartà
authors.affiliation: Department of Biomedical and Neuromotor Sciences; University of Bologna; Bologna, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bressanin
authors.affiliation: Institute of Molecular Genetics; National Research Council; Bologna, Italy; Muscoloskeletal Cell Biology Laboratory; IOR; Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.affiliation: Department of Biomedical and Neuromotor Sciences; University of Bologna; Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lonetti
authors.affiliation: Department of Human, Social, and Health Sciences; University of Cassino; Cassino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cappellini
authors.affiliation: Department of Biomedical and Neuromotor Sciences; University of Bologna; Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Institute of Molecular Genetics; National Research Council; Bologna, Italy; Muscoloskeletal Cell Biology Laboratory; IOR; Bologna, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Pediatric Oncology and Hematology Unit 'Lalla Seragnoli'; S. Orsola-Malpighi Hospital; University of Bologna; Bologna, Italy.
authors.forename: Fraia
authors.initials: F
authors.lastname: Melchionda
authors.affiliation: Pediatric Oncology and Hematology Unit 'Lalla Seragnoli'; S. Orsola-Malpighi Hospital; University of Bologna; Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.affiliation: Oncoematologia Pediatrica; IRCCS Ospedale Pediatrico Bambino Gesú; Rome, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: Oncoematologia Pediatrica; IRCCS Ospedale Pediatrico Bambino Gesú; Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Microbiology and Immunology; Brody School of Medicine; East Carolina University; Greenville, NC USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Biomedical and Neuromotor Sciences; University of Bologna; Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001372:Aza Compounds / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D051379:Mice; D058990:Molecular Targeted Therapy; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D001372:Aza Compounds; D018797:Cell Cycle Proteins; D003509:Cyclohexanecarboxylic Acids; D007211:Indoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013844:Thiazoles; D000097869:Polo-Like Kinase 1; C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; C544308:GSK 1070916; C576917:AURKA protein, human; C576921:AURKB protein, human
keywords: Aurora kinases; MEK/ERK/mTORC1; PI3K/Akt/mTORC2; T-ALL; apoptosis; caspases; cell cycle; polo-like kinases