Increased PD-L1 expression in KRAS mutated premalignant human bronchial epithelial cells is enhanced by LKB1 loss and mediated by ERK activation

Background PD-1/PD-L1 immune checkpoint pathway mediates tumor evasion from the immune system, and may be associated with poor prognosis in lung cancer. Activating KRAS mutations and LKB1 loss are common mutations in non-small cell lung carcinoma (NSCLC). Patients with mutated KRAS demonstrate less benefit from chemotherapy and resistance to approved targeted therapies. Inactivation of tumor suppressors commonly co-exist with KRAS mutations, and may contribute to tumor progression and treatment response. LKB1 is a tumor suppressor gene commonly inactivated in lung adenocarcinomas. The role of LKB1loss as a prognostic or predictive marker within human KRAS mutant NSCLC is unclear. There have been no therapeutic strategies that effectively target LKB1. Furthermore, the effect of these mutations on immune checkpoint immune regulation is poorly understood. KRAS mutations are known to activate the RAF-MEK-ERK pathway. We hypothesize that KRAS mutations directly regulate the PD-1/PD-L1 pathway and LKB1 loss may increase this effect through ERK activation.