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: Ribonucleotide reductase

Ribonucleotide reductase (RNR) is the key enzyme that catalyzes production of deoxyribonucleotides (dNTPs) for DNA replication and it also essential cancer cell proliferation. As RNR inhibitor, Gemcitabine widely used in therapies, however, resistance limits its therapeutic efficacy curative potential. Here, we identified mTORC2 a main driver gemcitabine non-small lung cancers (NSCLC). Pharmacological or genetic inhibition greatly enhanced induced cytotoxicity damage. Mechanistically, directly interacted phosphorylated large subunit RRM1 at Ser 631. Ser631 phosphorylation interaction with small RRM2 to maintain sufficient enzymatic activity efficient replication. Targeting retarded fork progression improved NSCLC xenograft model vivo. Thus, these results mechanism through regulating replication, conferring cells.