Unraveling Chemoresistance Mechanisms and Developing Targeted Strategies in Pancreatic and Lung Cancers

This dissertation investigates chemotherapy resistance and therapeutic innovation in non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC), with the goal of integrating mechanistic insights and drug discovery to improve treatment outcomes. It identifies oral bacteria as an important contributor to gemcitabine resistance through cytidine deaminase (CDD)-mediated drug inactivation, and further shows that bacterial host factors can regulate CDD activity. In addition, sustained c-MET activation and aberrant PKMYT1 expression are shown to be key drivers of resistance to nucleoside analogs. Based on these findings, the work proposes several intervention strategies, including inhibition of bacterial enzymes, modulation of the tumor microenvironment, and rational combination therapies. Tivantinib demonstrates synergistic effects with gemcitabine in PDAC, while PKMYT1 inhibition enhances RX-3117 sensitivity in NSCLC and supports PKMYT1 as both a therapeutic target and a predictive biomarker. Building on these mechanistic discoveries, the dissertation develops and evaluates novel small-molecule inhibitors targeting FAK, CDK1, and CDK7. The newly synthesized FAK inhibitors show strong anti-tumor activity in PDAC and NSCLC models by suppressing proliferation and migration, inducing apoptosis, and synergizing with EGFR-TKIs in NSCLC, with favorable in vivo tolerability. Novel CDK1 inhibitors derived from the marine natural product nortopsentin effectively inhibits growth in multiple PDAC models, including gemcitabine-resistant cells, and induces cell cycle arrest. Newly synthesized CDK7 inhibitors also exhibit potent anti-cancer effects in both PDAC and NSCLC, and notably trigger methuosis, a rare non-apoptotic cell death pathway, in NSCLC, with lysosomal involvement supported by transcriptomic and functional assays. Overall, this dissertation expands current understanding of chemotherapy resistance in NSCLC and PDAC and proposes multiple low-toxicity, translationally promising therapeutic strategies.