Synergistic effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway or NUP214-ABL1 fusion protein in human Acute Lymphoblastic Leukemia
Abstract
Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL) constitutes 25-30% of adult ALL cases, with its incidence increasing in individuals over 40 years old. Regardless of age, ABL1 fusion genes are associated with poor prognosis, and amplification of the NUP214-ABL1 oncogene is primarily observed in patients with T-ALL. T cell malignancies carrying ABL1 fusion genes demonstrate sensitivity to various cytotoxic agents, but complete remissions have not yet been achieved. The PI3K/Akt/mTOR signaling pathway, frequently activated in leukemias, plays a pivotal role in leukemogenesis.
This study evaluated the effects of three BCR-ABL1 tyrosine kinase inhibitors (TKIs)—Imatinib, Nilotinib, and GZD824—both as monotherapies and in combination with selective PI3K/Akt/mTOR inhibitors, on three NUP214-ABL1-positive T-ALL cell lines exhibiting PI3K/Akt/mTOR activation. The T-ALL cells were sensitive to BCR-ABL1 TKIs, which specifically targeted the ABL1 fusion protein but did not affect the PI3K/Akt/mTOR pathway. Four inhibitors targeting the PI3K/Akt/mTOR axis—GSK690693, NVP-BGT226, ZSTK474, and Torin-2—exhibited significant cytotoxic effects on T-leukemic cells, independently of the NUP214-ABL1 kinase and its associated pathways. Cytotoxicity was confirmed by the dephosphorylation of pAkt and pS6 proteins.
Both single-agent and combination treatments inhibited cellular viability, inducing concentration-dependent apoptosis, G0/G1 cell cycle arrest, and autophagy. Notably, combination therapies displayed synergistic cytotoxic effects. These findings suggest that co-targeting the NUP214-ABL1 fusion gene and the PI3K/Akt/mTOR signaling pathway may represent a promising therapeutic approach to improve outcomes in NUP214-ABL1-positive T-ALL patients.