Mirnome Exosomal Characterization Reveals A Distinct Signature Able To Predict Cisplatin-Response In Nsclc Patients.

Abstract Background: Non-small cell lung cancer (NSCLC) is one leading cause of death worldwide, with a 5-year survival rate of only 24%. Late diagnosis and the innate or acquired anti-cancer drug resistance are the main causes of this high mortality. In recent years, targeted drugs and immunotherapies have substantially increased the survival in aprox 15% of patients. However, the vast majority continue to receive the standard platinum-based chemotherapy (CDDP), although they present poor response to the treatment. Therefore, it is extremely important to identify new biomarkers for survival, prognosis and drug-resistance in NSCLC. Liquid biopsy represents a source of potentially actionable biomarkers, being minimally invasive and allowing to track tumor heterogeneity and detecting very early emergence of therapy resistance and recurrence. Among them, exosomal miRNAs are highly implicated in cancer progression and have great biomedical relevance due to their stability, feasible detection and their functional capacity to regulate gene expression. Methods: To study the implication of exosomal miRNAs in the induction of CDDP resistance, we analyzed the exosomal content of 3 paired CDDP sensitive and resistant lung cancer (H23S/R), and ovarian cancer (A2780S/R and 41M/R) cell lines by small RNAseq and we compared the profiles of the two phenotypes looking for candidates over-represented in the resistant cells-exosomes. Then, we performed a qRT-PCR validation of the candidates and studied their implication in the development of CDDP-resistance through its overexpression in our cell models and subsequent exposure to CDDP. Finally, we evaluated the clinical relevance of the validated candidates in lung, studying their expression levels in a prospective cohort of 51 advanced NSCLC patients and 10 healthy controls with a 3 years follow-up. Results: We identified 2 known miRNAs (miR1 miR2) and 1 novel miRNA (miR3) that were overexpressed in the exosomes of the resistant subtypes and validated in the lung cancer cell line H23. Among them, miR1 overexpression led to an increased sensitivity to CDDP in the H23 R phenotype. This could mean that resistant cancer cells are eliminating miR1 through exosomes to become more aggressive. Regarding exosomal miRNA expression in patients, the only miRNA that was differentially elevated in NSCLC patients vs controls was miR3, showing that it could be involved in the establishment of NSCLC. Then, we divided NSCLC patients in high and low miRNA expression levels, finding that bearing high levels of exosomal miR1 and miR2 extremely increased the risk of recurrence and death in NSCLC patients. Conclusions: We demonstrated that exosomal levels of miR1 and 2 would allow monitoring the prognosis and response to platinum in patients with advanced NSCLC, facilitating the choice of alternative therapies; and that miR3 in liquid biopsy could be useful as a biomarker for early diagnosis. Citation Format: Miranda Burdiel, Julia Jimenez, Carlos Rodriguez-Antolin, Olga Pernia, Rocio Rosas, Dario Sanchez-Cabrero, Patricia Cruz, Itsaso Losantos, Javier de Castro, Inmaculada Ibanez de Caceres. miRNome exosomal characterization reveals a distinct signature able to predict cisplatin-response in NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2381.