P3.03-28 LKB1 Mutation Status is Associated with Poor Radiation Outcome in Patients with Non-Small Cell Lung Cancer

Abstract

Previously, we reported that the upregulation of the NRF2/KEAP1 pathway in non-small cell lung cancers (NSCLC) bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis which contribute to radiation resistance in these tumors. Here, we explore the role of the LKB1 mutation as a potential predictor radiation outcome in NSCLC. We retrospectively analyzed the patients undergoing definitive treatment for newly diagnosed NSCLC who were enrolled in the prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI database according to LKB1 mutation status. Cox regression analysis and log-rank tests were used to correlate with radiation outcomes according to LKB1 mutation status and/or KRAS mutation subgroup. We then investigated the mechanisms of radiation resistance in these tumors in preclinical models. Of the 173 patients with stage III NSCLC treated with definitive radiotherapy, with or without chemotherapy were analyzed according to LKB1 mutation status demonstrated that LKB1 mutation had statistically significantly higher rate of loco-regional recurrence, and shorter disease-free survival than in patients with wild type LKB1 (P = 0.013 and P = 0.037, respectively). Moreover, additional loss of either LKB1 or TP53 in KRAS-mutant tumors renders these tumors higher loco-regional recurrence after radiation (P interaction = 0.045). We identified that LKB1 loss is associated with radio-resistance in part by KEAP1/NRF2 pathway activation. Re-expression of LKB1 or NRF2 pathway suppression (via KEAP1 expression) enhanced radiotherapy sensitivity in vivo. Our results suggest that LKB1 mutation is a potential predictive impact on radiation outcome of patients with NSCLC. The upregulation of the KEAP1/NRF2 pathway in NSCLC bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis and determine the sensitivity for radiation.