Introduction: In non-small cell lung cancer (NSCLC) LKB1 mutations combined with KRAS hyperactivation define a poor responsive, aggressive and disseminating phenotype. We recently unveiled the vulnerability of KRAS/LKB1 co-mutated (KL) patient-derived xenografts (PDXs) to metabolic stress-based treatments, and a clinical trial to test the efficacy of metformin and fasting-mimicking diet on KL NSCLC is currently ongoing in our Institute. Besides inactivating mutations, LKB1 functionality may be impaired by post-translation regulation. Because miR-17 is a potential epigenetic regulator of LKB1,we hypothesized that wild-type LKB1 (LKB1WT) NSCLC with high miR-17 expression may biologically and clinically mirror LKB1 mutated tumors.

Methods: NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion were selected, together with a panel of PDXs with high (LKB1WT/miR-17 high) or low (LKB1WT/miR-17 low) miR-17 expression. Taking advantage of series of NSCLC patients and PDXs, we retrospectively evaluated LKB1 and miR-17 expression levels in tumor tissue specimens. In addition, the TCGA dataset was interrogated for miR-17 expression and potential correlation with lung cancer clinical features.

Results: Direct targeting of miR-17 to LKB1 3’UTR was confirmed by luciferase reporter assay. We found that miR-17 overexpression in LKB1WT cell lines functionally impaired the LKB1/AMPK pathway, and prompted apoptotic response to metformin. Of note, LKB1WT/miR-17 high PDXs tumor cells showed a similar behavior upon metformin treatment. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression, and highlighted a prognostic role of miR-17 expression in LKB1WT patients, further confirmed by TCGA data analysis.

Conclusions: We validated miR-17 as epigenetic regulator of LKB1 expression in NSCLC tumors. We propose 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.

Citation Format: Cristina Borzi, Monica Ganzinelli, Elisa Caiola, Marika Colombo, Giovanni Centonze, Mattia Boeri, Laura Caleca, Ugo Pastorino, Mirko Marabese, Massimo Milione, Massimo Broggini, Marina C. Garassino, Gabriella Sozzi, Massimo Moro. LKB1 down-modulation by miR-17 biologically and clinically mirrors LKB1-mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1539.