Targeting the drug resistant state in cancer

In most cases, our best available therapies fail to durably eradicate advanced malignancies. Instead, over time, cancers re-emerge with acquired resistance to the agents used against them. In the past decade, work from our lab and others has demonstrated that resistance to a given agent can be driven by diverse molecular mechanisms, and that these mechanisms typically co-occur within individual patients. As a consequence, strategies to target individual resistance mechanisms are typically ineffective, while strategies to simultaneously target many diverse resistance mechanisms are too toxic to be administered to patients. This challenge has motivated work in our group to define new conceptual strategies to target resistance in cancer. In this talk, I will outline one such strategy, which involves the identification, characterization, and therapeutic targeting of ³collateral sensitivities² - therapeutic vulnerabilities that arise as a consequence of resistance evolution and which, in some cases, are shared across tumor cell clones driven by diverse resistance mechanisms. Our long term goal is to use these principles to define therapeutic strategies that have the unique ability to select against resistance evolution, and I will end my talk with empirical evidence of this concept.