A Promising Combination Treatment for Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) accounts for 15 to 20% of all adult leukemias worldwide. The management of this form of blood cancer has undergone a paradigm shift with the advent of imatinib, a breakthrough of targeted therapy, in the early 2000s. However, despite great improvement in the remission rate, a significant proportion of patients show resistance to the drug. Two recent studies led by prof. Marc Diederich, director of the fundamental research laboratory LBMCC, suggest a promising way around this obstacle: combining imatinib with another type of targeted medication : epigenetic modulators called HDAC inhibitors. These findings were published in Pharmaceutical Research and Clinical Epigenetics.

Also called chronic myelogenous leukemia, CML occurs as a result of a genetic change in early versions of certain blood-forming cells of the bone marrow, namely stem myeloid cells. This change forms an oncogene called BCR-ABL, which produces a protein of the same name with an abnormal tyrosine kinase (TK) activity that causes the cells to aberrantly grow, divide, and build up in the body. As a drug that blocks the effect of tyrosine kinase, a TK inhibitor (TKi), Imatinib has largely improved the management of CML. That is, in patients who do not develop resistance to TKis.


Combination therapy for combating imatinib drug resistance


Since monotherapy is frequently associated with drug resistance development, prof. Marc Diederich and fellow researchers from the LBMCC, the College of Pharmacy of the Seoul National University and the Faculty of Medecine of the Université de Lorraine, have engaged in investigations of combination therapy. As explained by prof. Diederich, “the idea is to associate imatinib with another set of molecules that will help weaken the cancer and make it more susceptible to treatment”. From this perspective, Histone Deacetylase (HDAC) inhibitors (HDACis) – a family of drugs which has already proved efficient in the treatment of other cancers –, seemed like a promising choice.


Deregulation of HDACs is a well-known player in the development of hematological malignancies such as lymphomas and other kinds of blood cancer. Associated with silencing gene expression, normal HDACs are epigenetic modulators that play a vital role in regulating important cellular functions, such as proliferation, cell-cycle regulation and programmed cell death (apoptosis). Deregulated oncogenic HDACs, however, do not perform these tasks properly, inducing disordered epigenetic regulation and cell proliferation. While inhibition of HDACs has demonstrated promising anti-cancer activities in other types of leukemia and lymphoma, relevance in the context of CML and in combination with imatinib essentially remained to be explored. 


HDACis help lower the activity of BCR-ABL and sensitize CML cells to imatinib


The present studies were led with different sets of HDAC inhibitors, one efficient for all kinds of HDACs using a pan-HDAC inhibitor called MAKV-8, the other targeting only HDAC type 6 using a specific inhibitor called compound 7b. In the first study, the researchers were able to demonstrate the HDAC inhibitory potential of compound MAKV-8 in vitro and in various CML cell lines. They showed that MAKV-8 in combination with imatinib displayed promising anti-cancer properties in imatinib-sensitive and imatinib-resistant CML cells, while moderately affecting healthy cells. Furthermore, the in vivo studies that were conducted on zebrafish demonstrated complete abrogation of tumor growth upon combined treatment with MAKV-8 and imatinib. While the mechanisms involved are different, essentially the same results were obtained in the second study. It was demonstrated that the HDAC6 inhibitor 7b alone induces BCR-ABL degradation and that combination with imatinib causes a synergistic anticancer effect in vitro and in vivo (in zebrafish again) and reduces the CML population.


Altogether, both sets of findings suggest that treatment with HDACis, whether MAKV-8 or compound 7b, contributes to a strong sensitization of imatinib-sensitive and imatinib-resistant CML cells. Collectively, the findings show that combination treatments with HDAC inhibitors and imatinib are likely to overcome drug resistance in CML pathology and thus constitute a rational basis to further study both these avenues of treatment to overcome TKI resistance in CML cells.

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Published in Clinical Epigenetics