Grant: Operating Grant

Clinical trials with targeted cancer therapeutics have demonstrated that the benefit of these agents is frequently limited to small groups of patients. Moreover, this benefit is often limited, due to the rapid development of resistance to drug actions. Thus, we need new biomarkers that can stratify patients who will respond to the therapy and ways to anticipate common resistance mechanisms. Understanding resistance mechanisms will help to optimize treatment options for patients to overcome drug resistance. In this proposal, we will uncover the molecular pathways that confer resistance to targeted cancer therapies, using unbiased genetic tools that allow us to manipulate the expression of many different genes in cancer cells. We will focus on mechanisms of drug resistance to several current inhibitors, which are currently used to treat many cancers including several subtypes of lung cancer. Candidate genes involved in the development of resistance will be investigated in a variety of model systems, including cell culture and mouse models of cancer, to identify the mechanisms by which they drive resistance. The expression of these candidate molecules will be examined in tumor samples of cancer patients to determine whether they are predictive of clinical response. Finally, our study will also provide potential treatment strategies to overcome drug resistance and result in clinical benefit for cancer patients.