Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia.
Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL) accounts for 25-30% of adult ALL and its incidence increases with age in adults >40 years old. Irrespective of age, the ABL1 fusion genes are markers of poor prognosis and amplification of the NUP214-ABL1 oncogene can be detected mainly in patients with T-ALL. T cell malignancies harboring the ABL1 fusion genes are sensitive to many cytotoxic agents, but up to date complete remissions have not been achieved. The PI3K/Akt/mTOR signaling pathway is often activated in leukemias and plays a crucial role in leukemogenesis.We analyzed the effects of three BCR-ABL1 tyrosine kinase inhibitors (TKIs), alone and in combination with a panel of selective PI3K/Akt/mTOR inhibitors, on three NUP214-ABL1 positive T-ALL cell lines that also displayed PI3K/Akt/mTOR activation. Cells were sensitive to anti BCR-ABL1 TKIs Imatinib, Nilotinib and GZD824, that specifically targeted the ABL1 fusion protein, but not the PI3K/Akt/mTOR axis. Four drugs against the PI3K/Akt/mTOR cascade, GSK690693, NVP-BGT226, ZSTK474 and Torin-2, showed marked cytotoxic effects on T-leukemic cells, without affecting the NUP214-ABL1 kinase and related pathway. Dephosphorylation of pAkt and pS6 showed the cytotoxicity of these compounds. Either single or combined administration of drugs against the different targets displayed inhibition of cellular viability associated with a concentration-dependent induction of apoptosis, cell cycle arrest in G0/G1 phase and autophagy, having the combined treatments a significant synergistic cytotoxic effect. Co-targeting NUP214-ABL1 fusion gene and PI3K/Akt/mTOR signaling pathway could represent a new and effective pharmacological strategy to improve the outcome in NUP214-ABL1 positive T-ALL.
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Carolina
C
Simioni
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Simona
S
Ultimo
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Alberto M
AM
Martelli
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Giorgio
G
Zauli
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Daniela
D
Milani
Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
James A
JA
McCubrey
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
Silvano
S
Capitani
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Luca M
LM
Neri
D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000068877:Imatinib Mesylate; D007093:Imidazoles; D028861:Nuclear Pore Complex Proteins; D051058:Oncogene Protein v-akt; D016374:Oncogene Proteins v-abl; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; C085914:NUP214 protein, human; C546842:MTOR protein, human; C498826:nilotinib
NUP214-ABL1; PI3K/Akt/mTOR signaling; T-Acute Lymphoblastic Leukemia; autophagy; targeted therapies