Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Abstract

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAblindependent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34 þ 38 lo ) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells in vitro. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34 þ cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease.

Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

“…[22][23][24] One such protein is myeloid cell leukemia-1, an important regulator of lymphocytic and hematopoietic stem cell survival. 13,[24][25][26] In human primary CML stem cells (CD34 ϩ 38 lo ), omacetaxine effectively induced apoptosis and impaired functionality of surviving stem cells as determined by colony-forming cell and long-term culture-initiating cell colony assays. However, both normal and non-CMLCD34 ϩ cells were sensitive to inhibition by omacetaxine.…”

“…However, both normal and non-CMLCD34 ϩ cells were sensitive to inhibition by omacetaxine. 26 The study presented here is the largest prospectively designed trial of CML patients with the T315I mutation reported to date. These patients were heavily pretreated and many had received multiple prior TKIs.…”

Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors

“…Franck E. Nicolini, 1 H. Jean Khoury, 2 Luke Akard, 3 Delphine Rea, 4 Hagop Kantarjian, 5 Michele Baccarani, 6 Janis Leonoudakis, 7 Adam Craig, 8 Annie-Claude Benichou, 8 …”

Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors

“…These results are in line with recent data on the stem cell activity of OM. 34 Whereas Allan et al explain the observed stem cell activity of OM in part by negative regulation of antiapoptotic molecules such as Mcl-2, OM might also prevent stem cell survival through interruption of cytokine-stimulated survival signals by depriving the leukemic cells from the cytokine receptor. As it has been shown that survival of CML stem cells does not depend on BCR-ABL-activity but on cytokines, targeting of cCRbc might be a means to overcome this Achilles heel of BCR-ABLdirected TKIs.…”