Baseline Extracellular Vesicle miRNA-30c and Autophagic CTCs Predict Chemoradiotherapy Resistance and Outcomes in Patients With Lung Cancer

Authors

Diego de Miguel-Perez
Francisco Gabriel Ortega
Rosario Guerrero Tejada
Antonio Martínez-Única
Christine B Peterson
Alessandro Russo
Muthukumar Gunasekaran
Andres F Cardona
Victor Amezcua
Jose Antonio Lorente
Jose Expósito Hernández
Christian Rolfo
Maria Jose Serrano

Publication Date

11-15-2023

Journal

Biomarker Research

Abstract

Concurrent chemoradiotherapy (cCRT) is the mainstay of treatment for patients diagnosed with locally advanced non-small cell lung cancer (NSCLC). One significant challenge in the effectiveness of this therapy is the potential development of resistance mechanisms, where autophagy up-regulation has been proposed as a key contributing factor. However, there is a lack of reliable biomarkers to predict outcomes on these patients. Interestingly, for addressing this gap, extracellular vesicles (EVs) and circulating tumor cells (CTCs) have emerged as potential sources of such biomarkers. In this study, we investigated EV-associated miRNAs and presence of autophagic CTCs in prospectively collected serial samples from 38 patients with stage III NSCLC undergoing cCRT. Our findings revealed that non-responders exhibited low levels of baseline EV miR-375, miR-200c, and miR-30c. In particular, EV miR-30c showed high predictive value with an area under the curve of 87.2%. Low EV miR-30c and the presence of autophagic-activated CTCs emerged as independent predictive biomarkers for shorter relapse-free survival and overall survival. Furthermore, in experimental models simulating the effects of chemo- and radiotherapy, the administration of miR-30c, either through direct transfection or encapsulation into human EVs, led to the inhibition of autophagy in these cells. This is the first report demonstrating that EV miR-30c inhibits tumor autophagy and its quantification, together with autophagic-activated CTCs, could be used as biomarkers for the stratification and monitoring of patients with NSCLC undergoing cCRT, and they may hold promising potential for guiding subsequent consolidation treatment with immunotherapy or other novel therapies based on autophagy inhibitors.

Keywords

Autophagy, Biomarkers, Chemoradiotherapy, Circulating tumor cells, Extracellular vesicles, Locally advanced non-small cell lung cancer, miRNAs

DOI

10.1186/s40364-023-00544-y

PMID

37968730

PMCID

PMC10652484

PubMedCentral® Posted Date

11-15-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes