Steven Grant, MD
Dr. Grant indicated no relevant conflicts of interest.
Corbin AS, Agarwal A, Loriaux M, et al. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011;121:396-409.
The development of imatinib mesylate, a prototypical targeted agent, has had a major impact on the treatment of patients with CML and other Bcr/Abl-related malignancies. Its use provides a paradigm for approaches that target oncoproteins to which transformed cells, such as CML, have become addicted. Nevertheless, despite initial success, most patients with CML develop resistance to imatinib, and those with advanced disease (e.g., accelerated phase or blast crisis) do not respond as well as those with chronic-phase disease. Resistance has been characterized as Bcr/Abl-dependent or Bcr/Abl-independent, depending upon whether addiction to the oncoprotein persists. Another complicating feature is that evidence suggests that primitive CML progenitors with stem cell characteristics appear to be less susceptible to imatinib than their more mature counterparts.1 This phenomenon may involve multiple mechanisms, including diminished drug transport, the quiescent state of stem cells, or the emergence of mutations rendering cells resistant to imatinib or second-generation agents.
However, the question of whether the Bcr/Abl tyrosine kinase of CML stem cells is truly resistant to imatinib has not been definitively established. This situation has changed with the report of Corbin et al. from Brian Druker’s lab in Oregon, who used a variety of techniques to determine whether such stem cells were truly resistant to imatinib-mediated kinase inhibition, manifested by diminished phosphorylation of Bcr/Abl, CRKL, and other downstream targets. Their findings, which were somewhat surprising, indicated that stem cells (e.g., CD34+, CD38-) were as vulnerable to kinase inhibition as more mature cells. In addition, quiescent cells, characterized by low Ki67 staining, also exhibited imatinib-mediated Bcr/Abl inhibition. Importantly, when cultured in the presence of growth factors, Bcr/Abl-inhibited CML stem cells were able to proliferate in the presence of imatinib to an extent comparable to their normal counterparts. The authors concluded that primitive CML progenitors were not addicted to Bcr/Abl and that therapies directed exclusively at Bcr/Abl are unlikely to eliminate CML stem cells.
The results of this study, while potentially of great significance, have some sobering implications. While circumventing Bcr/Abl-dependent forms of resistance to imatinib is hardly trivial, several approaches (i.e., developing more effective inhibitors, overcoming pharmacokinetic and pharmacodynamic barriers, etc.) come to mind. However, overcoming resistance in cells that are no longer addicted to Bcr/Abl is an entirely different matter; new approaches would have to be developed. In this context, the observation that HDAC inhibitors effectively enhance tyrosine kinase inhibitor activity against CML stem cells2 raises the possibility that these agents might in some way restore the addicted phenotype. It will be interesting to determine whether this is the case and, if so, by what mechanism. Assuming that CML stem cells make a tangible contribution to disease persistence, the results of the study by Corbin et al. suggest that entirely novel approaches that go beyond inhibiting Bcr/Abl will be required for future advances in CML therapy. To this end, it may be necessary to travel well beyond the canonical Bcr/Abl pathway.
- Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319-325.
- Zhang B, Strauss AC, Chu S, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010;17:427-442.
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