The introduction of the Bcr/abl kinase inhibitor imatinib mesylate (Gleevec) revolutionized treatment of CML and represents the prototype of molecularly targeted therapy. However, while imatinib continues to produce impressive clinical results, aside from a subset of patients who are eligible for stem cell transplantation, essentially all CML patients ultimately progress and die. This often reflects the development of Bcr/abl mutations or other forms of resistance. There is also speculation that while imatinib and other kinase inhibitors may eradicate the large majority of CML cells, they may permit CML stem cells to survive. This notion is supported by preclinical evidence that various clinically relevant Bcr/abl kinase inhibitors do not efficiently induce cell death in the most primitive CML stem cell compartment.1
Such considerations have prompted intense interest in the development of strategies specifically designed to eradicate CML stem cells. Some of these efforts have focused on disruption of developmental pathways. For example, recent studies suggest that, unlike imatinib, pharmacologic or genetic interruption of the hedgehog signaling pathway depletes CML stem cells,2 raising the possibility that a combined approach using Bcr/abl kinase inhibitors to eliminate the bulk of the leukemic cells with agents capable of eradicating CML stem cells may lead to improved therapeutic efficacy.
This article from the laboratory of Atsushi Hirao at Kanazawa University suggests an alternative and potentially complementary approach to eliminate CML stem cells. Akt is an important Bcr/abl downstream signaling molecule which promotes survival by negatively regulating Foxo family transcription factors. Using a murine syngeneic transplantation model, Naka et al. showed that leukemia-initiating cells (LICs) displayed diminished phosphorylation of Akt and increased nuclear localization of Foxo3A. Transgenic mice deficient in Foxo3A exhibited a significant impairment in the ability of LICs to induce disease, suggesting that Foxo3A plays a critical role in the maintenance of CML LICs. In addition, they showed that TGF-β negatively regulated Akt activation and thus promoted Foxo3A nuclear localization. An approach combining pharmacologic TGF-β inhibition and imatinib in the setting of Foxo3A deficiency was highly effective in eliminating CML stem cells and eradicating disease in vivo.
In Brief
These findings could have significant implications for efforts to elucidate mechanisms responsible for failure of conventional therapies to eradicate CML stem cells and may also provide important insights into new therapeutic strategies to overcome this problem. It is particularly interesting that activation of Akt, which is generally thought to contribute to Bcr/abl-mediated survival signaling, may paradoxically limit the maintenance of CML stem cells by suppressing Foxo3A. If validated, this could explain why standard Bcr/abl kinase inhibitors display a very limited capacity to eliminate the most primitive CML progenitor cells. Another important implication of these findings is that in order to achieve durable responses, and possibly cures, a multi-pronged approach targeting both stem cells and their more differentiated progeny may be necessary. For example, future chemotherapeutic approaches to this disease might involve co-administration of a Bcr/abl kinase inhibitor, particularly one active against cells bearing imatinib mesylate-resistant mutations, in conjunction with inhibitors of pathways required for CML stem cell maintenance. In this context, Hedgehog inhibitors have recently entered the clinical arena, and plans for such combination regimens are currently underway. Although inhibitors of the TGF-β/Foxo pathway are not yet in the clinic, studies such as the one by Naka et al. provide a strong rationale for their development. Their arrival is awaited with much anticipation.
References
Competing Interests
Dr. Grant indicated no relevant conflicts of interest.
