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FIGURE 7 5.2 Combination therapy strategies In recent years, the combination therapy strategy for gemcitabine resistance has made important breakthroughs, mainly focusing on the following directions: Targeted inhibition of RRM1 and synthetic lethality: Inhibitors of the large subunit of ribonucleotide reductase RRM1 (such as COH29) enhance efficacy through dual mechanisms: (1) inhibiting dNTP biosynthesis, (via RNR/RRM1 suppression), leading to depletion of intracellular dNTP pools notably with deoxycytidine triphosphate (dCTP) often being suppressed in multiple studies, though the magnitude of decrease varies by cell type, dose, and duration (Huff et al., 2022)

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Copper Metabolism Concerns Copper metabolism concerns represent theoretical risk of copper accumulation with prolonged use, though no documented cases of copper toxicity at recommended doses exist in literature

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