Investigation of Resistant Mechanisms of Apoptosis-inducing Anticancer Agents.

Cancer cells have acquired the ability to survive by up-regulating survival pathways or down-regulating cell death pathways that results in their resistance to apoptosis. Integral players involved in the activation or inhibition of apoptosis include the tumor suppressor p53 and the Bcl-2 family of proteins. In 50% of human cancers p53 is mutated resulting in inactivation of its tumor suppressor activity, however, in the remaining cancers p53 is functionally inhibited by its interaction with the MDM2 protein. This interaction has been extensively studied and has resulted in the discovery of small molecule MDM2-p53 interaction inhibitors like SAR405838. The Bcl-2 family of proteins, key regulators of apoptosis, has inspired a plethora of investigations aimed at targeting this family to activate apoptosis. Examples of these apoptosis-inducing agents are the Bcl-2/Bcl-xL inhibitors ABT-737 and ABT-263. Although these agents are currently in clinical trials for the treatment of cancer, it is fully expected that resistance to these drugs will develop. Despite impressive initial antitumor activity, the tumor regression achieved by ABT-737/ABT-263 and SAR405838 in xenograft models of acute leukemia is transitory; tumors eventually regrew after treatments were terminated, suggesting emergence of resistance to both drugs. Analysis of the regrown tumors initially treated with the inhibitors showed that the acute leukemia cells acquire resistance to SAR405838 by compromised function or mutation of p53, and to ABT-263 through down-regulation of pro-apoptotic Bcl-2 family member BAX. Combination and sequential treatment of SAR405838 and ABT-263 achieved longer term tumor regression than either agent alone in acute leukemia models. In the osteosarcoma model only in vitro exposure to SAR405838 resulted in acquired resistance whereas in vivo exposure did not. Analysis of the SJSA-1 cells that developed resistance in vitro to SAR405838 showed that p53 is mutated in the DNA binding domain resulting in resistance to SAR405838. Conversely, cell lines established from SAR405838 treated regrown tumors retained sensitivity to SAR405838. Taken together, these data suggest that both in vitro and in vivo models of resistance should be investigated in order to better identify resistance that may occur in a clinical setting.PhDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111332/1/giahoff_1.pd