The overall focus of the Doebele laboratory is the study of oncogene-targeted therapy in cancer. Initially our lab focused on a particular subtype of oncogenes termed gene fusions such as ALK, ROS1, RET in lung cancer, defining how cancer cells become resistant to oncogene targeted therapies.
Following the discovery of NTRK1 gene fusions in lung cancer and the realization that NTRK1/2/3 fusions occur across nearly tumor types, we pursued a novel idea that some therapies, for example those directed against oncogenes, could be developed using a tumor agnostic approach, an idea that has come to fruition with the FDA approval of larotrectinib for NTRK1/2/3 fusions in any adult or pediatric tumors. Clinical development of TRK inhibitors was supported using human-derived cell line models from our laboratory and supported by our generous patients who donate tissue and fluid samples for research. The CUTO3 (NTRK1 fusion positive) cell line was immensely useful in the rapid development of TRK inhibitors. Our library of cell lines has now grown rapidly and includes the first ever developed EGFR exon 20 insertion cell lines (CUTO14/17/18) that are being used by both academic laboratories and industry collaborators for new drug development in this difficult to treat subset.
Knowing that patient responses to therapy and emergent drug resistance mechanisms vary by patient, and thus one cell line model for each oncogene type cannot be representative, we are also building libraries of human derived cell line models for ALK, ROS1, RET and other oncogene subtypes to better understand interpatient heterogeneity for the development of new therapies.
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 have applied these approaches to ALK and ROS1+ lung cancer to elucidate novel mechanisms of drug resistance. Although much progress has been made on drugging kinase domain mutations that generate drug resistance, understanding how to detect and treat bypass signaling mechanism is an area of need. Ultimately, our goal is to advance personalized medicine through the identification, analysis, and rational targeting of driver oncogenes in cancer in order to improve the clinical outcomes of patients with this disease by understanding the adaptive mechanisms of cancer cells upon treatment.