Oncogene-independent resistance in Philadelphia chromosome - positive (Ph+) acute lymphoblastic leukemia (ALL) is mediated by activation of AKT/mTOR pathway
| Autor: | Syed Muhammad Areeb Ahmed, Usva Zafar, Afsar Ali Mian, Oliver G. Ottmann, El-Nasir Lalani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
4E-BP1 Antineoplastic Agents Jurkat Cells chemistry.chemical_compound hemic and lymphatic diseases Tumor Cells Cultured medicine Humans Philadelphia Chromosome Protein kinase B PI3K/AKT/mTOR pathway RC254-282 Original Research ABL Dose-Response Relationship Drug TOR Serine-Threonine Kinases Ponatinib Neoplasms. Tumors. Oncology. Including cancer and carcinogens Imatinib MTOR Inhibitors Oncogenes Precursor Cell Lymphoblastic Leukemia-Lymphoma BCR-ABL1 Dasatinib Adult Acute Lymphoblastic Leukemia chemistry Nilotinib Oncogene independent resistance Drug Resistance Neoplasm Cancer research AKT/mTOR pathway Proto-Oncogene Proteins c-akt Tyrosine kinase medicine.drug |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 9, Pp 1016-1027 (2021) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | Tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, and ponatinib have significantly improved the life expectancy of Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL) patients; however, resistance to TKIs remains a major clinical challenge. Point mutations in the tyrosine kinase domain (TKD) of BCR-ABL1 have emerged as the predominant cause of acquired resistance. In approximately 30% of patients, the mechanism of resistance to TKIs remains elusive. This study aimed to investigate mechanisms of nonmutational resistance in Ph+ ALL. Here we report the development of a nonmutational resistance cell line SupB15-RT; conferring resistance to approved ABL kinase inhibitors (AKIs) and allosteric inhibitors GNF-2, ABL001, and crizotinib, except for dasatinib (IC90 50nM), a multitarget kinase inhibitor. We found that the AKT/mTOR pathway is activated in these cells and their proliferation inhibited by Torin-1 with an IC50 of 24.7 nM. These observations were confirmed using 3 different ALL patient-derived long term cultures (PDLTCs): (1) HP (BCR-ABL1 negative), (2) PH (BCR-ABL1 positive and responsive to TKIs) and (3) BV (BCR-ABL1 positive and nonmutational resistant to TKIs). Furthermore, Torin-1 and NVP-BEZ235 induced apoptosis in PH and BV cells but not in HP cells. Our experiments provide evidence of the involvement of AKT/mTOR pathway in the evolution of nonmutational resistance in Ph+ ALL which will assist in developing novel targeted therapy for Ph+ ALL patients with BCR-ABL1 independent nonmutational resistance. |
| Databáze: | OpenAIRE |
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