mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer

• DOI: 10.1016/j.neo.2021.05.007
• Publication Date: 2021-06-12T00:11:42Z
• Authors: Ling Tian; Congcong Chen; Yanguan Guo; Fan Zhang; Jinye Mi; Qi Feng; Shengbin Lin; Naite Xi; Jiaxin Tian; Li Yu; Yan Chen; Mingrong Cao; Caiyong Lai; Jun Fan; Yongchang Zhang; Guo Chen
• Keywords: DNA Replication; 0301 basic medicine; Antimetabolites, Antineoplastic; Ribonucleoside Diphosphate Reductase; Mechanistic Target of Rapamycin Complex 2; Deoxycytidine; Histones; 03 medical and health sciences; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Ribonucleotide Reductases; Humans; Phosphorylation; Ribonucleotide reductase; mTORC2; RC254-282; Original Research; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Gemcitabine; DNA replication stress; 3. Good health; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Gene Knockdown Techniques; DNA Damage; Protein Binding; Signal Transduction

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.