When damaged or stressed, normal cells die via a carefully controlled process called apoptosis. In contrast, cancer cells keep dividing, often due to genetic errors that disrupt the mechanisms required to induce apoptosis. Dr. Eileen White from Rutgers University and colleagues examined the role of a molecule called BIM in tumorigenesis and chemotherapeutic response to paclitaxel, a drug that has been used successfully to treat breast, prostate, ovarian, and lung cancers. The researchers examined BIM because it has been implicated as a tumor suppressor and is known to play a role in the regulation of apoptosis.
The researchers found that BIM accumulation is absolutely required for paclitaxel-induced apoptosis, and that BIM deficiency is associated with paclitaxel-resistant tumors. Further research revealed that the H-ras/MAPK signaling pathway suppresses paclitaxel-mediated BIM induction by causing BIM to be targeted for destruction in proteosomes, thereby blocking the ability of BIM to induce apoptosis. Importantly, cotreatment with paclitaxel and a proteosome inhibitor currently approved for use in clinical trials restored paclitaxel-stimulated BIM accumulation and apoptosis that enabled tumor regression.
The H-ras/MAPK pathway is intimately linked to promotion of cell survival and is often abnormally activated during tumorigenesis. The researchers conclude that combinatorial chemotherapy using proteosome inhibitors to enhance chemosensitivity to paclitaxel in tumors where the H-ras/MAPK pathway is activated may be therapeutically beneficial.
These results suggest that a clear understanding of mechanisms underlying chemotherapeutic action and detailed knowledge of signaling mechanisms used by cancer cells can be used to guide rational decisions about combination therapy. According to Dr. White, "As it is not likely feasible to clinically test every possible combination of agents, the predictive value of knowing what drugs to use to treat specific cancer genotypes based on their mechanism of interaction can maximize the potential for effective treatment. Ultimately, successful therapy may rely upon relating tumor genotype to its capacity for response to specific agents, singly and in combination."
The other members of the research team include Ting-Ting Tan, Kurt Degenhardt, and Brian Beaudoin of Rutgers University; Deirdre A. Nelson of Howard Hughes Medical Institute and Rutgers University; Wilberto Nieves-Neira of Cancer Institute of New Jersey; Philippe Bouillet and Jerry M. Adams of The Walter and Eliza Hall Institute of Medical Research; Andreas Villunger of The Walter and Eliza Hall Institute of Medical Research and Innsbruck Medical University; and Eileen White of Howard Hughes Medical Institute, Rutgers University, and Cancer Institute of New Jersey. This work was supported by the Howard Hughes Medical Institute and a National Institutes of Health grant.
Ting-Ting Tan, Kurt Degenhardt, Deirdre A. Nelson, Brian Beaudoin, Wilberto Nieves-Neira, Philippe Bouillet, Jerry M. Adams, and Eileen White: "Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy"
Publishing in Cancer Cell, Volume 7, Number 3, March 2005, pages 227-238. http://www.cancercell.org
Journal
Cancer Cell