Alex M. Jaeger, PhD

Lung cancer remains the leading cause of cancer related death worldwide. Recently, a new class of drugs that target mutant KRAS has emerged with promising clinical results. As KRAS mutations are present in 20-30% of lung cancer patients, KRAS inhibitors are poised to be a mainstay in lung cancer treatment for years to come. However, while many patients exhibit initial responses to KRAS inhibitors, drug resistance remains a major barrier to curing patients. Some studies have suggested that KRAS inhibition activates an immune response, but the mechanisms driving this effect are unknown. We will conduct experiments focused on how KRAS inhibition changes the display of peptides (tiny proteins made of amino acids) to the immune system. Discovery of treatment induced peptides will set the stage for therapies that combine KRAS inhibitors with peptide-centric immunotherapies to combat resistance to this important class of lung cancer treatment.

Update: We have made significant progress in our first year. We collected high-quality data on immune-related proteins from human NSCLC cell lines and preclinical models and found major changes after KRAS inhibitor (KRASi) treatment. We also identified specific antigens that appear only when KRASi is used. In addition, we gathered a set of NSCLC patient samples, including both primary tumors and matched metastases, from people previously treated with KRASi. In the next phase of the project, we will combine data from cell lines, models, and patient samples to help design effective combinations of KRASi and immunotherapy for NSCLC.