Abstract
Abstract Mismatch Repair (MMR) deficiency occurs in some inherited and somatic malignancies as a consequence of mutation or epigenetic silencing. Since MMR-deficient tumours exhibit tolerance to many commonly used chemotherapeutic agents, there is an unmet clinical need to develop novel treatment strategies for this group of cancers. We utilized an in vitro isogenic colorectal model, the MLH1-deficient HCT116, and its isogenic comparator HCT116+Chr3, to perform high throughput screening of chemical libraries to identify novel drugs which were relatively cytotoxic to MLH1-deficient tumour cells compared with their MLH1-proficient comparators. The assay readout was cellular viability. ‘Hit’ drugs were then validated across a range of drug concentrations to determine the likelihood of ‘off target’ effects and potential clinical applicability, and further validated in clonogenic assays. Amongst the validated hits were cytosine arabinoside (ara-C), ethinyl oestradiol and desferoxamine. Ara-C was selected for further investigation and validated in two other in vitro models of MLH1 deficiency. Other nucleoside analogs were also investigated for MLH1-deficient selectivity and a lesser degree of selectivity was observed with gemcitabine. Compatible with the defective cell cycle checkpoints of MLH1-deficient cells, we have subsequently demonstrated that the excess cytotoxicity is associated with an increase in apoptosis that coincides with release from initial G1/early S phase arrest, suggesting that MLH1-deficient cells undergo mitotic catastrophe. In summary, we have used high throughput screening to identify possible new strategies for the treatment of MLH1-deficient cancers. Further mechanistic studies are ongoing. Combinations of drugs known to be MLH1-deficient selective are also being tested with a view to increasing the therapeutic window of a possible MLH1-deficient therapeutic strategy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 350. doi:10.1158/1538-7445.AM2011-350
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