SY05-01

Impaired apoptosis is both a critical step in the development of cancer and a major impediment to effective therapy. Bcl-2, the oncoprotein activated via the t14;18 chromosome translocation associated with human follicular lymphoma, inhibits cells from undergoing apoptosis in response to a variety of intracellular damage signals, including those evoked by radiation and chemotherapeutic agents. A score or so Bcl-2 relatives have now been identified in mammalian cells and, while the closest homologs (Bcl-xL, Bcl-w, Mcl-1 and A1) are also anti-apoptotic, others are instead pro-apoptotic. Bax and Bak are very similar to Bcl-2 in sequence, particularly in three conserved Bcl-2 Homology regions (BH1, BH2 and BH3) and, judging by Bax, also in structure. In contrast, the 'BH3-only proteins' are largely unrelated, apart from the signature BH3 domain that is essential for their killing function. Collectively, the Bcl-2 family functions as a 'life/death switch' that arbitrates whether or not a cell should activate the caspase-driven proteolytic cascade responsible for cellular demolition. Damage signals activate 'BH3-only' proteins, which bind to a hydrophobic groove on Bcl-2 and its pro-survival homologs, thereby neutralizing their capacity to prevent activation of Bax or Bak. Once activated, Bax and Bak permeabilize the outer mitochondrial membrane, releasing cytochrome c to trigger formation of the Apaf-1 scaffold required for activation of caspase-9. Activation of Bax and Bak requires neutralization of multiple pro-survival proteins (Willis et al, 2006) and while certain BH3-only proteins (eg Bim, Puma) can engage all the pro-survival proteins, others (eg Bad, Noxa) engage only subsets (Chen et al, 2005). There is now great interest in developing cancer therapeutics that can mimic the action of the BH3 domain by binding to pro-survival proteins to trigger the apoptotic program. Abbott has reported a very promising BH3 mimetic, ABT-737, which binds strongly to Bcl-2, Bcl-xL and Bcl-w, but not to Mcl-1 or A1 (Oltersdorf et al, 2005). While very effective against many follicular lymphomas, chronic lymphocytic leukemias and small cell lung cancers, most other tumors were refractory. Resistance to ABT-737 was shown to correlate with expression of Mcl-1 and its downregulation by a variety of strategies conferred sensitivity (van Delft et al, 2006). In vivo studies in a mouse lymphoma model suggest that this drug should be efficacious in tumors with low Mcl-1 levels or when combined with agents that inactivate Mcl-1, even in the face of Bcl-2 over-expression (van Delft et al, 2006; Mason et al, unpublished).

Chen, L., Willis, S.N., Wei, A., Smith, B.J., Fletcher, J.I., Hinds, M.G., Colman, P.M., Day, C.L., Adams, J.M. & Huang, D.C.S. (2005). Mol Cell, 17, 393-403.

Oltersdorf, T., Elmore, S.W., Shoemaker, A.R., Armstrong, R.C., Augeri, D.J., Belli, B.A., Bruncko, M., Deckwerth, T.L., Dinges, J., Hajduk, P.J., Joseph, M.K., Kitada, S., Korsmeyer, S.J., Kunzer, A.R., Letai, A., Li, C., Mitten, M.J., Nettesheim, D.G., Ng, S., Nimmer, P.M., O'Connor, J.M., Oleksijew, A., Petros, A.M., Reed, J.C., Shen, W., Tahir, S.K., Thompson, C.B., Tomaselli, K.J., Wang, B., Wendt, M.D., Zhang, H., Fesik, S.W. & Rosenberg, S.H. (2005). Nature, 435, 677-681.

van Delft, M.F., Wei, A.H., Mason, K.D., Vandenberg, C.J., Chen, L., Czabotar, P.E., Willis, S.N., Scott, C.L., Day, C.L., Cory, S., Adams, J.M., Roberts, A.W. & Huang, D.C.S. (2006). Cancer Cell, 10, 389-399.

Willis, S.N., Fletcher, J.I., Kaufmann, T., van Delft, M.F., Chen, L., Czabotar, P.E., Ierino, H., Lee, E.F., Fairlie, W.D., Bouillet, P., Strasser, A., Kluck, R.M., Adams, J.M. & Huang, D.C.S. (in press). Science.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA