Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia.

Carolina Simioni,Silvano Capitani,Simona Ultimo,Luca M Neri,Alberto M Martelli,James A Mccubrey,Daniela Milani,Giorgio Zauli

doi:10.18632/oncotarget.13035

Carolina Simioni, Silvano Capitani + Show 6 more

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https://doi.org/10.18632/oncotarget.13035

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Abstract

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.

Highlights

T-cell acute lymphoblastic leukemia (T-Acute Lymphoblastic Leukemia (ALL)) is an aggressive malignancy characterized by proliferation of thymocytes at various stages of development [1]
All the T-cell acute lymphoblastic leukemia (T-ALL) cells lines displayed phosphorylated Akt on both residues 473 and 308, the expression was lower in BE-13 cells (Figure 1)
BE-13 cells showed a weaker expression of the ribosomal S6 protein phosphorylated at Ser 235/236, which is a readout of mTORC1 activity, while in ALL-SIL and PEER cells basal expression of phosphorylated S6 protein was stronger

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by proliferation of thymocytes at various stages of development [1] This disease is reported in 10–15% of children and 25% of adult ALL patients, with a significant percentage of resistance to chemotherapy and an extremely poor prognosis in case of relapse [2, 3]. NUP214-ABL1 is a constitutively activated tyrosine kinase with oncogenic potential and has been discovered in approximately 6% of T-ALL cases It has been found on small, cytogenetically invisible, extrachromosomal elements (episomes), associated with TLX1 or TLX3 expression and deletion of CDKN2A [6]. Patients under treatment with these inhibitors frequently relapse for the onset of mutations [13] and it was recently reported that a NUP214-ABL1 positive patient treated with Imatinib, after obtaining a rapid remission, fatally relapsed [12]

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