COLUMBUS, Ohio – A new study led by researchers at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James) shows how tumors fail to be eradicated by therapy in lung cancer patients treated with targeted drugs called EFGR-tyrosine kinase inhibitors. It also suggests a way to improve the efficacy of therapy to slow or prevent resistance from developing. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are often used to treat lung cancers that have tumor cells with a mutation in the epidermal growth factor receptor (EGFR) gene. Patients who receive these agents often show dramatic improvement, but their cancers are never cured and tumors inevitably recur, leaving no good treatment options. This study found that in EFGR-mutated nonsmall-cell lung cancer, EGFR inhibitors activate a gene called Notch3. That protein then activates a molecule called beta-catenin, which in turn leads to the survival of cells in spite of treatment with EGFR-TKIs. It also showed in an animal model that combining an EGFR-TKI with a clinical beta-catenin inhibitor blocked the development of treatment-resistant cells, decreased tumor burden and improved recurrence-free and overall survival. The researchers report their findings in the journal Nature Communications. “We found that combining EGFR inhibitors and beta-catenin inhibitors is well tolerated and improves survival in EGFR-mutant animal models,” says principal investigator David Carbone, MD, PhD, professor of Medicine in the College of Medicine, Division of Medical Oncology, and the Barbara J. Bonner Chair in Lung Cancer Research at Ohio State. “The findings suggest that this combination of inhibitors may also improve survival in human EGFR-mutant lung cancer, and clinical trials are being planned.” In addition, the study suggested that a molecule called PAI1 might be a surrogate marker for poor outcome in patients receiving EFGR-TKI therapy, and that it might be a potential biomarker for selecting patients for beta-catenin-targeted therapy. “Overall, our findings provide a new understanding of the interaction of EGFR, Notch3 and beta-catenin that could improve the treatment of patients with EGFR-mutant lung cancer,” Carbone says. Funding from the NIH/National Cancer Institute (CA175370), Pelotonia and The DallaPezze Family Foundation supported this research. Other researchers involved in this study were Rajeswara Rao Arasada, Konstantin Shilo, Jianying Zhang, Rashelle Ghanem, Walter Wang, Tiffany Talabere, Shrilekha Misra, Wenrui Duan, Paolo Fadda, Mohammad A. Rahman, Patrick Nana-Sinkam10, Jason Evans, Joseph Amann, Elena E. Tchekneva and Mikhail M. Dikov, The Ohio State University; Tadaaki Yamada, Seiji Yano, Shinji Takeuchi and Koji Fukuda, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Nobuyuki Katakami, Institute of Biomedical Research and Innovation, Kobe, Japan; Keisuke Tomii, Kobe City Medical Center General Hospital, Kobe, Japan; Fumitaka Ogushi, National Hospital Organization National Kochi Hospital, Kochi, Japan; and Yasuhiko Nishioka, Tokushima University, Tokushima, Japan. About the OSUCCC – James The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 49 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by the NCI. As the cancer program’s 308-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. Media Contact: Amanda Harper OSUCCC – James Media Relations 614-685-5420 Amanda.Harper2@osumc.edu Written by: Darrell E. Ward Associate Director for Cancer Communications 614-293-3737 Darrell.Ward@osumc.edu