Exploiting microRNAs as circulating biomarkers and regulators of key targetable proteins to combat cancer chemoresistance

The limited availability of effective treatments and the generally poor prognosis associated with many cancer types highlight the pressing need for novel therapeutic approaches and new directions in chemoresistance research. Accordingly, this thesis aims to elucidate the mechanisms driving the development of chemoresistance and to identify potential vulnerabilities that may be exploited to improve the effectiveness of chemotherapy. Specifically, this work examines the role of microRNAs (miRNAs) in therapy resistance and evaluates their potential as diagnostic, prognostic, and predictive biomarkers in head and neck squamous cell carcinoma (HNSCC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC). Chapter 2 reviews the current knowledge of miRNAs in HNSCC, focusing on their roles in tumorigenesis and therapeutic potential. Chapter 3 reports novel findings on the oncogenic role of miR-96-5p in HNSCC and its contribution to resistance to chemotherapy and radiotherapy. Chapter 4 reviews recent advances and challenges in the use of EVs as biomarker and therapeutic delivery systems. Chapter 5 reports novel findings on plasma-derived EV miR-200 family members and evaluates their diagnostic potential in PDAC. Chapter 6 focuses on microRNAs implicated in resistance to gemcitabine and FOLFIRINOX in pancreatic ductal adenocarcinoma (PDAC) and examines miRNA-based therapeutic approaches. Chapter 7 investigates the therapeutic potential of combining tivantinib, a c-MET inhibitor, with gemcitabine in PDAC. Chapter 8 reviews emerging treatment strategies for small cell lung cancer that extend beyond immunotherapy. Chapter 9 examines the mechanisms underlying resistance to the nucleoside analog RX-3117 in lung cancer and proposes approaches to improve its therapeutic efficacy.