What is the role of RRM1 in the mechanism of action of NUC-1031 and its clinical implications?

Label:chem

Topic
The RRM1 subunit of ribonucleotide reductase is involved in the conversion of nucleotide diphosphates to their deoxyform. Gemcitabine-derived dFdCDP can bind to RRM1, inhibiting its function and altering nucleotide pools. NUC-1031, like gemcitabine, can bind to RRM1, potentially enhancing its anticancer effects.
Answer
NUC-1031 binds to the RRM1 subunit of ribonucleotide reductase, inhibiting its function and disrupting nucleotide pools. This binding can enhance DNA damage by reducing the availability of deoxynucleotides required for DNA replication. However, increased RRM1 expression in response to treatment can mitigate this effect. Clinically, RRM1 expression levels in tumor tissues have been suggested as a prognostic biomarker, with lower RRM1 expression correlating with better survival outcomes in some cancer types. However, the study found no conclusive correlation between RRM1 expression and survival across multiple cancers, likely due to the low number of biopsies and heavily pre-treated patient population.
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