Identifying genetically-supported drug repurposing targets for non-small cell lung cancer through mendelian randomization of the druggable genome

Background: Lung cancer is responsible for most cancer-related deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of cases. Targeted therapy has made promising advancements in systemic treatment for NSCLC over the last two decades, but inadequate drug targets with clinically proven survival benefits limit its universal application in clinical practice compared to chemotherapy and immunotherapy. There is an urgent need to explore new drug targets to expand the beneficiary group. This study aims to identify druggable genes and to predict the efficacy and prognostic value of the corresponding targeted drugs in NSCLC. Methods: Two-sample mendelian randomization (MR) of druggable genes was performed to predict the efficacy of their corresponding targeted therapy for NSCLC. Subsequent sensitivity analyses were performed to assess potential confounders. Accessible RNA sequencing data were incorporated for subsequent verifications, and Kaplan-Meier survival curves of different gene expressions were used to explore the prognostic value of candidate druggable genes. Results: MR screening encompassing 4,863 expression quantitative trait loci (eQTL) and 1,072 protein quantitative trait loci (pQTL, with 453 proteins overlapping) were performed. Seven candidate druggable genes were identified, including CD33, ENG, ICOSLG and IL18R1 for lung adenocarcinoma, and VSIR, FSTL1 and TIMP2 for lung squamous cell carcinoma. The results were validated by further transcriptomic investigations. Conclusions: Drugs targeting genetically supported genomes are considerably more likely to yield promising efficacy and succeed in clinical trials. We provide compelling genetic evidence to prioritize drug development for NSCLC.