Caratterizzazione della regolazione e della funzione di PRODH in adenocarcinoma del polmone: un ruolo per i recettori tirosin chinasici?

Lung cancer is a global health concern. Targeted therapies improve survival and, among them, Epidermal Growth Factor Receptor (EGFR) inhibitors (TKIs) is used for lung adenocarcinoma (ADC) treatment. However, variable response and resistance mechanisms invariably occur. We hypothesized that PRODH, an enzyme key in proline catabolism, played a role in EGFR-mutant lung ADCs, since we previously found a correlation with PRODH expression. Overexpressing wild-type or mutant EGFR constructs led to decreased PRODH levels in various cell lines, with the EGFR p.E746-A750del mutant showing the strongest effect construct. EGFR inhibition in cell lines harboring the p.E746-A750del EGFR mutation increased PRODH mRNA, confirming that EGFR negatively regulates PRODH expression. Bioinformatic analysis identified putative response elements for STAT3, a signaling molecule downstream of EGFR, in PRODH intron 1. We show that STAT3 indeed mediates EGFR modulation of PRODH. PRODH repression may represent a mechanism by which EGFR, via STAT3, contributes to tumor progression. This project also aimed to advance the knowledge on PRODH’s role in lung cancer progression. We observed increased PRODH expression in two EGFR-mutant lung ADC cell lines with in-vitro acquired resistance to TKIs compared to their TKI-sensitive counterparts. PRODH inhibition affected 2D/3D-growth of TKI-resistant but not TKI-sensitive cells. Our results suggest different PRODH functions at different lung cancer stages.