Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate below 10%. Gemcitabine based chemotherapy remains the standard therapy, but its efficacy is limited by drug resistance. KRAS mutations (>90%) are a major driver of PDAC therapy resistance, although KRAS-targeted strategies showed limited efficacy. PDAC is also characterized by a dense desmoplastic stroma enriched in tumor-associated macrophages (TAMs) that impair treatment efficacy. Our previous work identified TAMs-derived CHI3L1 as a mediator of drug resistance. Our published work demonstrated that the isoquinolinequinone N-oxide (IQQ) RK2 and RK3 exhibit potent antitumor activity against drug-resistant lung and colon cancer cells. Preliminary data also shows activity in KRAS-mutated PDAC cell lines, including drug-resistant models. Importantly, these compounds may target CHI3L1 due to structural similarity with known inhibitors. This project aims to evaluate the antitumor activity of RK2 and RK3 in PDAC, elucidate their molecular mechanisms and targets, and assess their chemosensitizing effects to gemcitabine treatment, generating evidence to support future xenograft studies.