A Drug Cocktail May Be Needed To Cure Leukemia

It is the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease have caused problems with its use.

Investigators at the British Columbia Cancer Agency (Vancouver, BC, Canada) have reported in a paper published in the October 20, 2008, online edition of the Journal of Experimental Medicine that they had identified a CML protein that inhibits imatinib activity. This protein, AHI-1, which is highly expressed in CML stem cells, was found to prevent imatinib from blocking the activity of the abnormally fused BCR-ABL tyrosine kinase that is characteristic of CML cells.

The investigators showed that expressing AHI-1 in stem cells turned the cells cancerous in vitro, and that these cells caused lethal leukemia when transferred into mice. When expressed in BCR-ABL­positive cells, AHI-1 stimulated cancer cell formation. Blocking the synthesis of AHI-1 in cancer cells from imatinib-resistant CML patients restored the ability of the drug to kill the cells.

The growth-promoting activity of AHI-1 was attributed to its ability to bind to BCR-ABL. Research is now aimed at finding a drug to block AHI-1. The need for both a tyrosine kinase inhibitor such as imatinib as well as an AHI-1 blocker suggests that the cure for CML and other leukemias may not lie in a single miracle drug, but rather in a carefully concocted cocktail of targeted therapies.

Related Links:
British Columbia Cancer Agency