Yves Chabu, University of Missouri, USA est invité par José Gomes (IBGC) pour un séminaire organisé par le département Sciences Biologiques et Médicales (université de Bordeaux) le 11 septembre à 14h en salle de conférence de l’IBGC. Le séminaire sera également diffusé en visioconférence.

« Targeting Extracellular Vesicles to Overcome Drug Resistance in Lung Cancer »

The 5-year survival rate for patients with metastatic Non-small Cell Lung Cancer (NSCLC) is ~7% compared to 92% for early-stage asymptomatic disease. Most NSCLC patients present with advanced stage inoperable disease at initial diagnosis. Logically, early disease detection represents a direct path for improving patients’ survival. Current lung cancer screening (chest imaging by low dose computed tomography/LDCT) is not sensitive enough to reliably detect early disease due to its low sensitivity and high false positive rate. Undetected patients progress and develop NSCLC that ultimately become resistant to any of the currently available therapy options. The development of screening strategies that permit early NSCLC interception and/or override drug resistance in later disease stages will extend patients life.

Plasma extracellular vesicle (EV) and circulating microRNA (miRNA) are emerging as cancer biomarkers. Tissues-derived EV are deposited in the blood circulation system and can be readily isolated from peripheral blood. However, the identification of highly sensitive core miRNA signatures remains a challenge. We integrated EV and circulating blood miRNA analyses in samples derived from screening controls and NSCLC patients. This approach identified combined features (circulating + EV miRNAs abundance) that robustly differentiate NSCLC cancer patients not only from disease-free screening controls but also from LDCT over diagnosed individuals.

Based on tumor mutational features, confirmed NSCLC patients are stratified to chemotherapy or targeted therapy or immunotherapy. However, the magnitude, depth, and duration of response remain limited.  For example, oncogenic activation of the Epidermal Growth Factor Receptor EGFR are potent NSCLC drivers in ~18% of patients. Tyrosine kinase inhibitors that specifically target mutated EGFR generate substantial clinical benefits for EGFR-mutated patients. However, nearly all patients develop drug resistance and relapse. Strategies that improve patient stratification and disarm TKI-resistance mechanisms are needed. We found that NSCLC circulating miRNAs and EV cooperatively promotes NSCLC resistance to potent chemotherapy and TKI.  Finally, preliminary findings highlighting a role for EV in lung cancer immune escape and resistance to immunotherapy will be discussed.

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