Exploring new therapeutic options for chemoresistant locally advanced lung cancer

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. About one third of NSCLC patients present at diagnosis with locally advanced disease (stage IIIA) which are characterized by lymph node metastases. For this group of patients, neoadjuvant chemotherapy (NACT) followed by surgery is the best therapeutic option. However, clinical response to NACT is heterogeneous including patients with a complete eradication of lymph node metastases (pN0), and patients with persistent disease (pN2). Of note, 9pN09 patients showed a favourable prognosis (~50-60% survival, at 5-year) when compared to 9pN29 patients (~20-30% survival, at 5-year). Methods: To identify new molecular determinants involved in NACT response, we recently performed whole-microRNA expression profiling of metastatic lung tumor cells, which were collected from mediastinal lymph nodes before NACT either by endobronchial ultrasound transbronchial aspiration (EBUS-TBNA) (n=11) or mediastinoscopy (n=41). In addition, we performed a meta-analysis of a cohort (n=84) of NSCLC (i.e. The Cancer Genome Atlas LUAD and LUSC dataset) with complete follow-up. Results: We found a set of 20 miRNAs significantly differentially expressed in pN2 vs. pN0 tumors. Hierarchical clustering analysis using this 20-miRNA set revealed a clear separation of pN0 patients from pN2 patients. However, when the 20-miRNA set was used in the primary NSCLCs from TCGA dataset, the chemoresponsive and chemoresistant tumors could not be stratified. This possibly suggests unique properties of this 20-miRNA set and their modulated target genes in metastatic cells, and in the acquisition of a chemoresistant phenotype. Furthermore, by coupling miRNA and mRNA expression profile in metastatic samples, we rewired i) cancer intrinsic gene networks with a role in chemotherapy resistance, and ii) an augmented infiltration of tumor promoting immune cell populations (TILs). Conclusions: Lung cancer metastases are intrinsically distinct and there exist molecular subtypes with different NACT response, identifiable by miRNA expression profile. Future efforts will be directed to identify the landscape of molecular mechanisms mediated by miRNAs, including the modulation of TILs possibly involved in the acquired chemoresistance. Citation Format: Roberto Cuttano, Elisa Dama, Valentina Melocchi, Tommaso Colangelo, Cristiano Carbonelli, Giorgia Maroni, Elena Levantini, Fabrizio Bianchi. Exploring new therapeutic options for chemoresistant locally advanced lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1792.