ArticleNeoplasia (New York, N.Y.)2021
mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer.
Article in Neoplasia (New York, N.Y.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- Regulation of ferroptosis in colorectal cancer through therapeutic modulation and miRNA targeting.Biochemistry and biophysics reports · 2026Article
- Targeted metabolism creates possibilities for lung cancer treatment in the precision tumor era.Respiratory research · 2026Review
- Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance.Cells · 2026Review
- ENO1-mediated deoxycytidine synthesis and gemcitabine resistance by stabilizing RRM2 in pancreatic cancer.Cell death & disease · 2025Article
- DEAD/H-box RNA helicase 10 promotes pancreatic cancer cell proliferationWorld journal of gastrointestinal oncology · 2025Article
- The Role of PI3K/AKT/mTOR Signaling in Tumor Radioresistance and Advances in Inhibitor Research.International journal of molecular sciences · 2025Review
- RRM1 O-GlcNAcylation inhibition suppresses pancreatic cancer via TK1-mediated replication stress.Cancer gene therapy · 2025Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- Targeting CK2-mediated phosphorylation of p53R2 sensitizes BRCA-proficient cancer cells to PARP inhibitors.Oncogene · 2023Article
- Targeting the biology of aging with mTOR inhibitors.Nature aging · 2023Review
- SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair.Disease markers · 2022Article
- KIF20A is associated with clinical prognosis and synergistic effect of gemcitabine combined with ferroptosis inducer in lung adenocarcinoma.Frontiers in pharmacology · 2022Article
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ribonucleotide reductase (RNR) is the key enzyme that catalyzes the production of deoxyribonucleotides (dNTPs) for DNA replication and it is also essential for cancer cell proliferation. As the RNR inhibitor, Gemcitabine is widely used in cancer therapies, however, resistance limits its therapeutic efficacy and curative potential. Here, we identified that mTORC2 is a main driver of gemcitabine resistance in non-small cell lung cancers (NSCLC). Pharmacological or genetic inhibition of mTORC2 greatly enhanced gemcitabine induced cytotoxicity and DNA damage. Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. Targeting mTORC2 retarded DNA replication fork progression and improved therapeutic efficacy of gemcitabine in NSCLC xenograft model in vivo. Thus, these results identified a mechanism through mTORC2 regulating RNR activity and DNA replication, conferring gemcitabine resistance to cancer cells.
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