Abstract 4386: CETSA as a new strategy to understand efficacy, adverse effects and resistance development of anticancer drugs

Abstract

Abstract A key step of the action of most drugs is their binding (engagement) of the target protein(s). However, limitations in the available methods for directly accessing this critical step have added uncertainties in many stages of drug development. We have developed a generic method for evaluating drug binding to target proteins in cells and tissues (Martinez Molina et al. Science, 341:84). The technique is based on the physical phenomenon of ligand-induced thermal stabilization of target proteins; the method is therefore called the cellular thermal shift assay (CETSA). The technique allows for the first time to directly measure the biophysical interactions between a drug and protein target in non- engineered cells and tissues. We show that using CETSA a range of critical factors for drug development can be addressed at the target engagement level, including drug transport and activation, off-target effects, drug resistance as well as drug distribution in cells, patient and animal tissues. Using quantitative mass-spectrometry, proteome-wide CETSA has been established which allows for off-target effects as well as downstream biochemistry to be discovered (Savitsk et al. Science, 346, 6205:1255784). Together the data supports that CETSA is likely to become a valuable tool for developing and understanding the action of cancer drugs in the future. Citation Format: Pär Nordlund, Sara Lööf, Henritte Laursen, Anette Öberg, Johan Lengqvist, Rozbeh Jafari, Lingyun Dai, Ka DIam Go, Nayana Prabhu, Radoslaw Sobota, Andreas Larsson, Anna Jansson, Chris Heng Tan Soon, Lekshmy Sreekumar, Yan Ting Lim, Daniel Martines Molina. CETSA as a new strategy to understand efficacy, adverse effects and resistance development of anticancer drugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4386.