Oxaliplatin resistance in pancreatic ductal adenocarcinoma is non‑significantly mediated by diminished drug uptake but is highly linked to a poor apoptotic response to the cytotoxic threat

Pancreatic ductal adenocarcinoma (PDAC) resistance to oxaliplatin is associated with diminished drug uptake and a poor molecular apoptotic response; however, the relative contribution of each of these modes of resistance remains unclear. Accordingly, PDAC cell lines (AsPC‑1 and BxPC‑3) and human patient‑derived organoids (hPDOs; h08 and h19) were assessed in the present study, with proliferation assays, atomic absorption spectroscopy‑based quantification of intracellular oxaliplatin, luminogenic caspase 3/7 assays, PCR array‑based transcriptomic analysis and RNA sequencing performed to scrutinize the oxaliplatin resistance phenotype. Notably, AsPC‑1 cells [half maximal inhibitory concentration (IC$_{50}$), 88.8±45 µM were 4.2‑fold more oxaliplatin resistant than BxPC‑3 cells (IC$_{50}$, 21±0.7 µM; P=0.02)]. In addition, when normalized to intracellular platinum levels, AsPC‑1 cells remained 2.5‑fold more resistant than BxPC‑3 (the fold difference was decreased by 40% from 4.2‑fold to 2.5‑fold; P=0.21). In hPDOs, resistant h19 took up oxaliplatin 22% less efficiently than sensitive h08, and the nominal resistance difference was 3.5‑fold, and it remained at 2.8‑fold after controlling for drug accumulation (the fold difference was decreased by 20% from 3.5‑fold to 2.8‑fold; P=0.34). ... mehrThese findings indicated that diminished drug uptake non‑significantly contributed to oxaliplatin resistance, which was in agreement with the rather minor differences in drug transporter expression levels (including ATP7A and ATP7B). Furthermore, when challenged with identical intracellular oxaliplatin levels, AsPC‑1 cells exhibited delayed caspase 3/7 activity initiation, weaker induction of pro‑apoptotic genes BBC3 (1.7‑fold vs. 5‑fold) and PMAIP (2.5‑fold vs. 6‑fold), but stronger enhancement of anti‑apoptotic Jun expression (7‑fold vs. 3‑fold) than BxPC‑3 cells. Taken together, oxaliplatin resistance in PDAC models may be highly linked to a poor apoptotic response, whereas drug uptake seems to be of minor relevance.