RRM1 inhibition sensitizes lung adenocarcinoma to decitabine treatment

Aberrant DNA methylation has been implicated in tumorigenesis and development of lung cancer. However, Nucleoside analog DNA methyltransferase inhibitors have demonstrated clini-cal utility in treatment of myelodysplastic syndrome and acute myeloid leukemia, the drugs have not shown commensurate clinical efficacy in solid tumors. Mechanisms mediating the primary resistance to DNA hypomethylating agents in solid tumors are not fully understood. Here, we hy-pothesized that factors that limit incorporation of nucleoside analog DNA methyltransferase in-hibitors in genomic DNA may underlie the tumor cell intrinsic primary resistance to decitabine in lung cancer. We found that RRM1 expression levels were inversely correlated with decitabine incorporation rates detected by LC-MS/MS. RNA interference mediated depletion of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), or pharmacological inhibition of RNR signifi-cantly potentiated inhibition of lung cancer cell clonogenic survival in vitro and xenograft growth in vivo by decitabine treatment. Additionally, RRM1 knockdown or pharmacological inhibition of RNR enhanced decitabine mediated upregulation of tumor suppressor genes and STING-related im-mune response. RNR inhibition led to increased incorporation of decitabine into genomic DNA by reducing the availability of dCTP. These findings nominate the promising combination therapy of decitabine and RNR inhibitors as being ripe for further clinical translation.