LKB1 mutations in NSCLC are associated with KEAP1/NRF2-dependent radiotherapy resistance targetable by glutaminase inhibition

Purpose Radiotherapy (RT) with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes. Experimental design We conducted a retrospective analysis of 194 patients with stage I-III NSCLC including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with RT, and assessed loco-regional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating RT resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain. Results In Stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P = 0.0108), and shorter DFS (HR 2.530, P = 0.0029) and OS (HR 2.198, P = 0.0263). LKB1 loss promoted relative resistance to RT which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to RT. Conclusions These data provide evidence that LKB1 loss is associated with local-regional recurrence and poor clinical outcomes in NSCLC patients treated with RT and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.