The Doebele Laboratory
The overall focus of the Doebele laboratory is the study of oncogene-targeted therapy in cancer. Our lab focuses on a particular subtype of oncogenes termed gene fusions, which include ALK, ROS1, RET and NTRK1/2/3. Our lab generates cell line models of these cancers from human tumor biopsies. Utilizing these patient-derived models, we use genetic, proteomic and bioinformatic approaches to elucidate both the sensitivity and cellular resistance to oncogene-targeted therapy. We also perform resistance testing on patient tumor samples following the development of drug resistance and model these putative resistance mechanisms in the laboratory. We have applied these approaches to ALK and ROS1+ lung cancer to elucidate novel mechanisms of drug resistance. Our lab first identified NTRK1 gene fusions in lung cancer and have developed novel biomarkers to detect these genetic alterations, including the use of proximity ligation assays (PLA) to detect kinase-adaptor signaling complexed in vitro, in vivo, and in situ. We have also generated the pre-clinical data that has led to the development of clinical trials for TRK inhibitors that are now ongoing. Currently, our lab is focusing on defining additional cancer cell liabilities that can be targeted before acquired resistance develops to diminish or delay drug resistance. Ultimately, our goal is to advance personalized medicine through the identification, analysis, and rational targeting of driver oncogenes in lung cancer in order to improve the clinical outcomes of patients with this disease by understanding the adaptive mechanisms of cancer cells upon treatment.