Scientists are making progress toward unraveling the molecular mysteries that underlie cancer progression and treatment resistance. Two studies in the November 2006 issue of the journal Cancer Cell, published by Cell Press, provide mechanistic details that may explain why the small-molecule chemical ABT-737 is emerging as a unique and effective anticancer agent. The studies also demonstrate that pharmacological manipulation of specific signaling molecules can make resistant cancer cells sensitive to treatment with ABT-737. These studies provide support for the idea that examination of the molecular profile of individual tumors can provide useful information for guiding treatment decisions.
Cell survival molecules like BCL-2 are abnormally regulated and overactive in many tumors and are thought to promote cancer progression and protect cancer cells from cancer therapies. In normal cells, BH3 proteins bind to and inhibit BCL-2. Therefore, researchers have attempted to design compounds that are similar to these natural antagonists to use as weapons against cancer cells. The synthetic BH3 mimetic ABT-737 has been shown to interact strongly with BCL-2 but weakly with other BCL-2 family members, such as MCL-1, and has been described as an excellent candidate for further research.
Dr. Michael Andreeff from The University of Texas M.D. Anderson Cancer Center and colleagues found that ABT-737 effectively kills acute myeloid leukemia (AML) cells without affecting normal blood cells. However, the researchers observed that cancer cells with high levels of the cell survival molecule MCL-1 were much less sensitive to ABT-737 treatment. Further experiments demonstrated that pharmacologic inhibition of MCL-1 or inhibition of MCL-1 through RNA interference restored sensitivity of leukemic cells and definitively identified MCL-1 as an ABT-737 resistance factor. The researchers suggest that specific BCL-2 family proteins may define resistance to this BH3 mimetic.
In a separate study, Dr. David C.S. Huang from The Walter and Eliza Hall Institute of Medical Research in Australia and colleagues demonstrated that resistant cells can be sensitized to ABT-737 by using varied approaches that destabilize or inactivate MCL-1. Dr. Huang's group concludes that ABT-737 should be effective against tumors that exhibit BCL-2 overexpression and low MCL-1 levels or when used in combination with MCL-1 inhibitors. "The mechanistic insights provided here suggest ways in which ABT-737 might be used efficaciously as a single agent and in combination therapy. Our studies provide a rational basis for designing clinical trials of this highly promising agent and a benchmark for systematically evaluating BH3 mimetic compounds," writes Dr. Huang.
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