Abstract KN1: Finding mechanisms and biomarkers of drug resistance in cancer
René Bernards · Clinical Cancer Research · 2010
Abstract Unresponsiveness to therapy remains a significant problem in the treatment of cancer, also with the new classes of targeted therapeutics. In my laboratory, we use functional genetic approaches to identify biomarkers that can predict responsiveness to clinically relevant cancer therapeutics. We focus on targeted cancer drugs such as trastuzumab (Herceptin), PI3K inhibitors, MEK inhibitors, ALK inhibitors, mTOR inhibitors, Histone Deacetylase inhibitors and retinoic acid. These drug target specific molecules or pathways that are often activated in cancer. Nevertheless, it remains poorly explained why a significant number of tumors do not respond to the therapy. We aim to elucidate the molecular pathways that contribute to unresponsiveness to targeted cancer therapeutics using a functional genetic approach. This will yield biomarkers that may be useful to predict how individual patients will respond to these drugs. Furthermore, this work may allow the development of drugs that act in synergy with the established drug in the treatment of cancer. To identify biomarkers that control tumor cell responsiveness to cancer therapeutics, we use two complementary approaches. First, we use genome wide loss-of-function genetic screens (with shRNA interference libraries) in cancer cells that are sensitive to the drug-of-interest to search for genes whose down-regulation confers resistance to the drug-of-interest (resistance screens). In addition, we use single well siRNA screens with a low dose of the drug to screen for genes whose inhibition enhances the toxicity of the cancer drug (sensitizer screens). Once we have identified resistance and/or sensitizer genes, we ask if their expression is correlated with clinical response to the drug-of-interest using tumor samples of cancer patients treated with the drug in question, whose response to therapy is documented. Examples of genetic screens to identify mechanisms of resistance to different cancer drugs will be presented. Citation Information: Clin Cancer Res 2010;16(7 Suppl):KN1