Abstract
Resistance to imatinib (Gleevec®) in cancer cells is frequently because of acquired point mutations in the kinase domain of BCR-ABL. Ponatinib, also known as AP24534, is an oral multi-targeted tyrosine kinase inhibitor (TKI), and it has been investigated in a pivotal phase 2 clinical trial. The histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) has been evaluated for its significant clinical activity in hematological malignancies. Thus, treatments combining ABL TKIs with additional drugs may be a promising strategy in the treatment of leukemia. In the current study, we analyzed the efficacy of ponatinib and vorinostat treatment by using BCR-ABL-positive cell lines. Treatment with ponatinib for 72 h inhibited cell growth and induced apoptosis in K562 cells in a dose-dependent manner. We found that ponatinib potently inhibited the growth of Ba/F3 cells ectopically expressing BCR-ABL T315I mutation. Upon BCR-ABL phosphorylation, Crk-L was decreased, and poly (ADP-ribose) polymerase (PARP) was activated in a dose-dependent manner. Combined treatment of Ba/F3 T315I mutant cells with vorinostat and ponatinib resulted in significantly increased cytotoxicity. Additionally, the intracellular signaling of ponatinib and vorinostat was examined. Caspase 3 and PARP activation increased after combination treatment with ponatinib and vorinostat. Moreover, an increase in the phosphorylation levels of γH2A.X was observed. Previously established ponatinib-resistant Ba/F3 cells were also resistant to imatinib, nilotinib, and dasatinib. We investigated the difference in the efficacy of ponatinib and vorinostat by using ponatinib-resistant Ba/F3 cells. Combined treatment of ponatinib-resistant cells with ponatinib and vorinostat caused a significant increase in cytotoxicity. Thus, combined administration of ponatinib and vorinostat may be a powerful strategy against BCR-ABL mutant cells and could enhance the cytotoxic effects of ponatinib in those BCR-ABL mutant cells.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative disorder of hematopoietic stem cells caused by the presence of the BCR-ABL oncogene in the so-called Philadelphia chromosome (Ph) [1]
Since vorinostat was effective against T315I mutant cells, we investigated whether ponatinib-resistant cells were inhibited by this HDAC inhibitor (HDACi)
Ponatinib is effective against T315I mutant cells that are resistant to imatinib and second-generation ABL tyrosine kinase inhibitor (TKI) nilotinib and dasatinib
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative disorder of hematopoietic stem cells caused by the presence of the BCR-ABL oncogene in the so-called Philadelphia chromosome (Ph) [1]. The BCR-ABL fusion protein is a constitutively active tyrosine kinase and activator of downstream molecules such as Myc and signal transducer and activator of transcription (STAT) [2,3]. BCR-ABL activity promotes the growth of leukemic cells and enhances malignant expansion of hematopoietic stem cells. The clinical outcome for patients with CML is improved by imatinib mesylate (GleevecH) [4]. Imatinib was the first ABL tyrosine kinase inhibitor (TKI) that was identified to reduce BCRABL kinase activity. Some patients developed resistance to imatinib, which could be attributed to point mutations in the kinase domain of BCR-ABL [5].
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