Non-coding RNA driving chemoresistance in pancreatic cancer: Mechanisms of resistance to FOLFIRINOX and its components 5-fluorouracil and oxaliplatin

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. This is mainly due to intrinsic and acquired resistance to chemotherapy. The FOLFIRINOX regimen (5-fluorouracil, oxaliplatin, irinotecan, leucovorin) is a standard treatment for PDAC patients with good performance status. However, the efficacy of this regimen is limited by chemoresistance. Notably, 5-fluorouracil (5-FU) and oxaliplatin are core components of FOLFIRINOX, and resistance mechanisms identified for these individual agents may collectively contribute to resistance against the full regimen. Emerging evidence implicates non-coding RNAs (ncRNAs), as critical regulators of chemoresistance mechanisms. Methods In this review, we synthesized findings from published studies investigating the role of ncRNAs in modulating sensitivity or resistance to FOLFIRINOX, as well as to its individual components 5-FU and oxaliplatin, in PDAC. Data were extracted from experimental studies and clinical sample analyses, focusing on ncRNA expression changes, validated molecular targets, downstream signaling pathways, and functional outcomes. Results For the full FOLFIRINOX regimen, upregulated miR-181a-5p (targeting ATM), miR-1307 (regulating CLIC5/DNA damage pathways), and lncRNA SNHG7 (Notch1/Jagged1/Hes-1 signaling) promote resistance. Regarding 5-FU, which forms the fluoropyrimidine backbone of FOLFIRINOX, multiple upregulated miRNAs (miR-21/PTEN/PDCD4; miR-221/CDK6; miR-296-5p/BOK; miR-181c/YAP/TAZ; miR-183/PTEN/PI3K/Akt; miR-320a/PDCD4; miR-499a-5p/PTEN/PI3K/Akt) and lncRNAs (TUG1/miR-376b-3p/DPD; SCAMP1/miR-106a-5p/AGK) promote resistance, while downregulated miRNAs (miR-137/PTN; miR-138-5p/vimentin; miR-34a/Bcl-2/Notch; miR-494/SIRT1/c-myc) and lncRNAs (GAS5/miR-181c-5p/Hippo; DGCR5/miR-320a) increase sensitivity. For oxaliplatin, the platinum component of FOLFIRINOX, upregulated miR-181a-5p (ATM), lncRNA UPK1A-AS1 (IL8/Ku70/Ku80), and circRNAs circABCC4 (PKM2/KPNA2) and circBIRC6 (SUMOylation of XRCC4) drive resistance. Many of these mechanisms—particularly those involving DNA damage response (ATM, XRCC4), apoptosis regulation (BOK, PDCD4, Bcl-2), and drug metabolism (DPD)—may synergistically contribute to FOLFIRINOX resistance. Conclusions ncRNAs are central regulators of chemoresistance in pancreatic cancer, functioning through diverse mechanisms including DNA damage response modulation, apoptosis evasion, and drug metabolism alteration. Mechanistic studies on 5-FU and oxaliplatin resistance directly inform our understanding of FOLFIRINOX resistance, as these agents constitute the therapeutic backbone of the regimen. These ncRNAs represent potential therapeutic targets and predictive biomarkers for overcoming resistance. Future strategies should focus on validating whether targeting these ncRNAs resensitizes PDAC cells to the full FOLFIRINOX regimen and developing ncRNA-based combination therapies for clinical translation.