IHC-based predictive biomarker for irinotecan response.

548 Background: For gastro-intestinal cancers, irinotecan is used as first or second line, either as single agent or in combination therapy. The patient response rate is low and drug resistance mechanism is not understood. Irinotecan like other topoisomerase I inhibitors (camptothecin and their analogues, CPTs) are not MDR substrates, topoI mutations are rare and other potential mechanisms have not been validated. One of the most distinct cellular responses to CPT is the proteolytic degradation of topoI by the ubiquitin proteosomal pathways (UPP) and the rate of topoI degradation determines the drug response. Using a functional proteomic approach we have defined the mechanism of UPP mediated topoI degradation and have identified the molecular determinant of CPT resistance. We have demonstrated that higher basal level of topoI-pS10 drives rapid topoI ubiquitination and degradation in response to CPT. Methods: We have raised mouse monoclonal antibody that specifically binds with topoI-pS10 for immunohistoch...