Proteomic Characterization Reveals CYP2S1 as a Mediator of Drug Resistance in PDAC.

OBJECTIVES: The aim is to investigate the proteomic profile of different molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) and understand their impact on patient outcomes, particularly focusing on pathways involved in xenobiotic metabolism and drug resistance. MATERIALS AND METHODS: The study utilized the serum-free PACO cell culture model and a quantitative prefractionation-based MALDI/MS approach to establish the proteomic profiles of various PDAC subtypes. Differential protein regulation was analyzed to identify systematic alterations in metabolic and drug resistance pathways. Mechanistic studies involved the knockdown and overexpression of key proteins to assess their role in drug resistance. RESULTS: Proteomic analysis revealed subtype-specific alterations, particularly in pathways associated with xenobiotic metabolism and drug resistance. Notably, CYP2S1, a member of the CYP450 family, was upregulated in the HNF1A+ PDAC subtype. CYP2S1 levels were further inducible by polyaromatic hydrocarbons (PAHs) and SN38, the active metabolite of irinotecan via AHR. Mechanistic studies demonstrated that knockdown of AHR or CYP2S1 sensitized PDAC cells to SN38, whereas overexpression of CYP2S1 increased resistance to SN38. CONCLUSIONS: The findings highlight the significant role of CYP2S1 in mediating drug resistance in certain PDAC subtypes. Targeting CYP2S1 and its regulatory pathways could enhance the efficacy of chemotherapeutic agents like irinotecan in treating PDAC. These results provide new insights into the molecular mechanisms underlying PDAC subtype-specific drug resistance and suggest potential therapeutic targets.