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However, Nucleoside analog DNA methyltransferase inhibitors have demonstrated clinical utility in the 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 hypothesized that factors that limit incorporation of nucleoside analog DNA methyltransferase inhibitors in genomic DNA may underlie the tumor cell intrinsic primary resistance to decitabine (DAC) in lung cancer. We found that RRM1 expression levels were inversely correlated with DAC incorporation rates detected by LC\u2013MS\/MS. RNA interference-mediated depletion of RRM1, the catalytic subunit of ribonucleotide reductase (RNR), or pharmacological inhibition of RNR significantly potentiated inhibition of lung cancer cell clonogenic survival in vitro and xenograft growth in vivo by DAC treatment. Additionally, RRM1 inhibition enhances DAC-mediated tumor suppressor gene reactivation and STING pathway activation via DNA damage-induced IFI16 sensing. RNR inhibition led to increased incorporation of DAC into genomic DNA by reducing the availability of dCTP. These findings nominate the promising combination therapy of DAC and RNR inhibitors as being ripe for further clinical translation.<\/jats:p>","DOI":"10.1038\/s41419-026-08522-6","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T22:24:36Z","timestamp":1772144676000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["RRM1 inhibition sensitizes lung adenocarcinoma to decitabine treatment"],"prefix":"10.1038","volume":"17","author":[{"given":"Nan","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Vaghasia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Anders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Rudek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-0730","authenticated-orcid":false,"given":"William G.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0744-6606","authenticated-orcid":false,"given":"Srinivasan","family":"Yegnasubramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-0166","authenticated-orcid":false,"given":"Jianya","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"8522_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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