LKB1 down-modulation by miR-17 identifies NSCLC patients with worse prognosis eligible for energy-stress based treatments

Abstract Introduction Preclinical models recently unveiled vulnerability of LKB1/KRAS co-mutated non-small cell lung cancer (NSCLC) to metabolic stress-based treatments. Since miR-17 is a potential epigenetic regulator of LKB1, we hypothesized that wild type LKB1 NSCLC with high miR-17 expression may be sensitive to energetic stress condition, and eligible for metabolic frailties-based therapeutic intervention. Methods We took advantage of NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion, and of patient-derived xenografts (PDXs) with high (LWT/miR17H) or low (LWT/miR17L) miR-17 expression. We evaluated LKB1 pathway impairment and apoptotic response to metformin. We retrospectively evaluated LKB1 and miR-17 expression levels in tissue specimens of NSCLC patients and PDXs. In addition, a lung cancer series from TCGA dataset was analyzed for miR-17 expression and potential correlation with clinical features. Results We identified miR-17 as epigenetic regulator of LKB1 in NSCLC and confirmed targeting of miR-17 to LKB1 3’UTR by luciferase reporter assay. We showed that miR-17 overexpression functionally impairs the LKB1/AMPK pathway. Metformin treatment prompted apoptosis upon miR-17-overexpression only in LKB1WT cell lines, as well as in LWT/miR17H PDXs. Retrospective analysis in NSCLC patients revealed an inverse correlation between miR-17 and LKB1 expression and highlighted a prognostic role of miR-17 expression in LKB1WT patients, which was further confirmed by TCGA data analysis. Conclusion We identified miR-17 as a mediator of LKB1 expression in NSCLC tumors. This study proposes a miR-17 expression score potentially exploitable to discriminate LKB1WT NSCLC patients with impaired LKB1 expression and poor outcome, eligible for energy-stress based treatments.