Cotreatment with Vorinostat (Suberoylanilide Hydroxamic Acid) Enhances Activity of Dasatinib (BMS-354825) against Imatinib Mesylate–Sensitive or Imatinib Mesylate–Resistant Chronic Myelogenous Leukemia Cells

Abstract

Purpose: We determined the effects of vorinostat [suberoylanilide hydroxamic acid (SAHA)] and/or dasatinib, a dual Abl/Src kinase (tyrosine kinase) inhibitor, on the cultured human (K562 and LAMA-84) or primary chronic myelogenous leukemia (CML) cells, as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and kinase domain-mutant forms of Bcr-Abl. Experimental Design: Following exposure to dasatinib and/or vorinostat, apoptosis, loss of clonogenic survival, as well as the activity and levels of Bcr-Abl and its downstream signaling proteins were determined. Results: Treatment with dasatinib attenuated the levels of autophosphorylated Bcr-Abl, p-CrkL, phospho-signal transducer and activator of transcription 5 (p-STAT5), p-c-Src, and p-Lyn; inhibited the activity of Lyn and c-Src; and induced apoptosis of the cultured CML cells. Combined treatment of cultured human CML and BaF3 cells with vorinostat and dasatinib induced more apoptosis than either agent alone, as well as synergistically induced loss of clonogenic survival, which was associated with greater depletion of Bcr-Abl, p-CrkL, and p-STAT5 levels. Cotreatment with dasatinib and vorinostat also attenuated the levels of Bcr-AblE255K and Bcr-AblT315I and induced apoptosis of BaF3 cells with ectopic expression of the mutant forms of Bcr-Abl. Finally, cotreatment of the primary CML cells with vorinostat and dasatinib induced more loss of cell viability and depleted Bcr-Abl or Bcr-AblT315I, p-STAT5, and p-CrkL levels than either agent alone. Conclusions: As shown here, the preclinical in vitro activity of vorinostat and dasatinib against cultured and primary CML cells supports the in vivo testing of the combination in imatinib mesylate^sensitive and imatinib mesylate^resistant CML cells.

Dasatinib-responsive Chronic Lymphocytic Leukemia in a Patient Treated for Coexisting Chronic Myeloid Leukemia

“…Although dasatinib is a tyrosine kinase inhibitor (TKI) that is effective against Bcr-Abl to a similar extent as imatinib and is also useful for suppressing leukemogenesis in patients with CML, the medication was originally developed as a pan-Src kinase inhibitor. In vitro, the drug inhibits Lyn kinase and induces apoptosis of K562 cell lines by inhibiting Lyn phosphorylation (29). The Src family kinases, including Lyn kinase, are overexpressed in CLL patients and appear to play crucial roles in the proliferation and survival of cancer (30).…”

Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

“…8,[26][27][28] A first success in this direction was achieved by combining specific kinase inhibitors with agents impairing transcription and/or translation: decreased proliferation of leukemia cell lines and primary CML cells, including those harboring T315I mutant were observed in in vitro and ex vivo experiments. [29][30][31] Embracing the idea of influencing tumor signaling pathways and cell-cycle check points at the same time, monotherapy with small molecule inhibitors targeting specific key enzymes simultaneously seems a desirable approach in the treatment of CML.…”

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

“…Data is emerging which reveals Src kinase as a novel tumour target, where its inhibition is effective at suppressing proliferation and/or metastatic events in a wide range of tumour types including CML [30,31], colon tumours [32,33] and pancreatic cancer [34,35]. Further studies [36,37] also provide compelling evidence that targeting Src may be of value in combination with existing chemotherapy to provide an augmented antitumour response. In breast cancer cells, Src is implicated as a key element in non-genomic, oestrogen-induced MAPK and MMP activation [16,38,39] and oestrogen-mediated cellular proliferation and cell-cycle progression [40,41].…”