Cellular Responses to Anticancer Therapies

Previous and current research
Many anticancer therapies rely for their success on the induction of DNA damage or the inhibition of nucleic acid metabolism. In response to such insults, cells typically activate checkpoint mechanisms that arrest the cell cycle and enhance cell survival, in part by inhibiting the key mitotic regulatory protein kinase Cdc2. My postdoctoral work included a detailed investigation of Cdc2 regulation. We are now studying the molecular mechanisms of checkpoint arrest , with a view to understanding the factors that determine the degree of effectiveness of anticancer agents. Unfortunately the success of chemotherapy is frequently limited by the emergence of drug resistant tumour cells. Our second major interest is a novel pathway of drug resistance that involves AP-1 transcription factors, eIF3 subunits and proteasome-associated proteins. These are conserved from yeast to humans, allowing rapid genetic analysis of what may be an important aspect of clinical drug resistance.

Future projects
We hope to gain a more thorough understanding of the basis of cell cycle arrest following DNA damage or inhibition of replication, and to explore the therapeutic potential of drugs related to caffeine and staurosporine that can bypass this arrest and thus lead to Cdc2 activation. Tumour cells lacking p53 may be specifically sensitive to such drugs administered after DNA damage. In collaboration with Takashi Toda (Cell Regulation Laboratory) we hope to identify conserved molecular targets for checkpoint-overriding drugs and to develop yeast-based screens for novel agents of this sort. Continued investigation of the proteasome / AP-1 pathway will allow us to determine the importance of this pathway in clinical drug resistance, with a view to the development of specific resistance-reversal agents.