Pancreatic Ductal Adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a highly aggressive disease with a 5-year survival rate of less than 10%. The KRAS oncogene is mutated in nearly 95% of PDAC and is considered a near universal driver of the disease. There are exciting new drugs targeting KRAS entering the clinical arena, but acquired resistance is still a major problem. Our research has demonstrated that RAS signaling post-translationally activates the MYC oncoprotein, increasing its protein stability and oncogenic activity. Using a large dataset of human PDAC we found that MYC activity is linked to aggressive, liver metastatic PDAC. We generated a novel KRAS-MYC mouse model of PDAC, which displays metastasis mimicking the human disease. Through omic analyses of paired biopsies in a window-of-opportunity clinical trial targeting KRAS signaling we identified MYC activation as an important resistance mechanism to KRAS inhibition. Using a clinically available MYC inhibitor, OMO103, we show increased treatment efficacy with combination of KRAS and MYC inhibition in metastatic PDAC. Together, our work contributes to understanding and treatment of the most aggressive form of pancreatic cancer.

Dr. Sears received her Bachelor’s degree in Biology from Reed College (1986), Portland Oregon. She received her Ph.D. in Cell Biology from Vanderbilt University (1993), Nashville Tennessee, and conducted her post-doctoral studies at Duke University in the Genetics Department. Dr. Sears is a full professor in the Department of Molecular and Medical Genetics at Oregon Health & Science University. She is Co-Director of the Brenden-Colson Center for Pancreatic Care and the Inaugural Krista L. Lake Chair in Cancer Research. Dr. Sears is also a senior member in the Knight Cancer Institute. She has received funding from the National Institutes of Health, the Department of Defense, and several other foundations. She has received both research and business innovation awards in the areas of cancer biology, therapeutics, and technology advancement. Dr. Sears’ research expertise is in cancer systems biology focused on dynamic regulation of cellular signaling pathways that control tumor cell phenotype and tumor-stromal cell cross-talk underlying tumor fitness. Her lab uses complex patient-derived 3D bioprinted tumor models, human tumor xenografts, and genetically engineered mouse tumor models to reveal underlying tumor biology and mechanisms of drug resistance.