Background: MET dysregulation has been implicated in the development of primary and secondary resistance to EGFR tyrosine kinase inhibitor (TKI) therapy. However, the clinicopathological characteristics and outcomes of patients harboring EGFRsensitive mutations and de novo MET amplifications still need to be explored. Methods: A total of 54 patients from our hospital with non-small cell lung cancer harboring EGFR-sensitive mutations and/or de novo MET amplifications were included in this study. Survival rates were estimated by the Kaplan-Meier method with logrank statistics. Lung cancer organoids (LCOs) were generated from patient-derived malignant pleural effusion to perform drug sensitivity assays. Results: Fifty-four patients with the appropriate clinicopathological characteristics were enrolled. MET FISH was performed in 40 patients who were stratified accordingly into two groups: EGFR+/METamp-(n = 22) and EGFR+/METamp + (n = 18). Survival rates for EGFR+/METamp-and EGFR+/METamp + patients respectively, were as follows: the median progression-free survival (PFS) was 12.1 and 1.9 months (p<0.001); the median post-progression overall survival (pOS) was 25.6 and 11.6 months (p = 0.023); the median overall survival (OS) was 33.2 and 12.7 months (p = 0.013). Drug testing conducted in LCOs derived from malignant pleural effusion from EGFR+/METamp + patients showed that dual targeted therapy was more effective than TKI monotherapy. Conclusion: EGFR+/METamp + patients treated with first-line TKI monotherapy had poor clinical outcomes. Dual targeted therapy showed potent anticancer activity in the LCO drug testing assay, suggesting that it is a promising first-line treatment for EGFR+/METamp + patients. Randomized controlled trials are needed to further validate these results.K E Y W O R D S de novo MET amplification, EGFR-sensitive mutation, non-small cell lung cancer, patient-derived organoid, targeted therapy Kai-Cheng Peng and Jun-Wei Su contributed equally.

Background. Despite increasing understanding of m6A-related lncRNAs in lung cancer, the role of m6A-related lncRNAs in the prognosis and treatment of lung squamous cell carcinoma is poorly understood to date. Thus, the current study aims to elucidate its role and build a model to predict the prognosis of LUSC patients. Materials and Methods. The data of the current study were accessed from the TCGA database. Pearson correlation analysis was performed to identify lncRNAs correlated to m6A. Next, an m6A-related lncRNAs risk model was built using a single factor, least absolute association, selection operator, and multivariate Cox regression analysis. Results. The relevance between 23 m6A genes and 14,056 lncRNAs is shown by Pearson correlation analysis by Sankey diagram. Multivariate Cox regression analysis determined that 11 m6A-lncRNAs show predictive potential in prognosis, which is confirmed by the consistency index, Kaplan–Meier analysis, principal component analysis, and ROC curve. Additionally, the immune analysis showed that the enrichment of immune cells, major histocompatibility complex molecules, and immune checkpoints in the high and low-risk subgroups were markedly disparate, with the high-risk group showing a stronger immune escape ability and a worse response to immunotherapy. Conclusion. In conclusion, the risk model based on m6A-related lncRNAs showed great promise in predicting the prognosis and the efficacy of immunotherapy.