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

Tian, Ling; Chen, Congcong; Guo, Yi; Zhang, Fan; Mi, Jinye; Qi, Feng; Lin, Shengbin; Xi, Naite; Tian, Jiaxin; Yu, Lan; Chen, Yan; Cao, Mingrong; Lai, Caiyong; Fan, Jun; Zhang, Yongchang; Guo, Chen

doi:10.1016/j.neo.2021.05.007

Cited by 7 publications

(3 citation statements)

References 35 publications

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“…Thus, HR activity could determine the PARP inhibitor sensitivity in cancer cells. We utilized the HR repair reporter system, which harbors an engineered GFP gene inactivated by insertion of the I-SceI endonuclease recognition site [ 26 ]. Only after the I-SceI-induced DSB is repaired by HR repair pathway, active GFP can be restored ( Figure 1(a) ).…”

Section: Resultsmentioning

confidence: 99%

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair

Lin

Tian

et al. 2022

Disease Markers

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As a multifunctional protein posttranslational modification enzyme in eukaryotic cells, Poly-ADP-ribose polymerase (PARP) acts as a DNA damage sensor, which helps to repair DNA damage through recruiting repair proteins to the DNA break sites. PARP inhibitors offer a significant clinical benefit for ovarian cancer with BRCA1/2 mutations. However, the majority of ovarian cancer patients harbor wild-type (WT) BRCA1/2 status, which narrows its clinical application. Here, we identified a small compound, SN-38, a CPT analog, which sensitizes BRCA-proficient ovarian cancer cells to PARP inhibitor treatment by inhibiting homologous recombination (HR) repair. SN-38 treatment greatly enhanced PARP inhibitor olaparib induced DNA double-strand breaks (DSBs) and DNA replication stress. Meanwhile, the combination of SN-38 and olaparib synergistically induced apoptosis in ovarian cancer. Furthermore, combination administration of SN-38 and olaparib induced synergistic antitumor efficacy in an ovarian cancer xenograft model in vivo. Therefore, our study provides a novel therapeutic strategy to optimize PARP inhibitor therapy for patients with BRCA-proficient ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair

Lin

Tian

et al. 2022

Disease Markers

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“…Another nucleotide synthesis-related enzyme modulated by mTORC2 is the ribonucleotide reductase (RNR). mTORC2 phosphorylates RNR, which catalyzes the production of dNTPs for DNA replication [ 283 ]. mTORC2 phosphorylation of RNR large subunit RRM1 at Ser631 enables its interaction with small subunit RRM2 to enhance RNR catalytic activity and efficient DNA replication.…”

Section: Targets and Cellular Functions Of Mtorc2mentioning

confidence: 99%

The mTORC2 signaling network: targets and cross-talks

Ragupathi,

Kim,

Jacinto

2024

Biochemical Journal

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The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

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“…Some mechanisms related to GEM resistance have been disclosed in recent years. For example, mTORC2 helps NSCLC cells evade GEM-induced cell death by regulating Ribonucleotide reductase activity and DNA replication ( Tian et al, 2021 ). Coordinated metabolic reprogramming of HIF-1α/ABCB6 promotes reactive oxygen species (ROS) clearance directly contributing to the inhibition of apoptosis in tumor cells and the promotion of GEM resistance in NSCLC cancer ( Xiang et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

KIF20A is associated with clinical prognosis and synergistic effect of gemcitabine combined with ferroptosis inducer in lung adenocarcinoma

Liang

Huang

et al. 2022

Front. Pharmacol.

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Gemcitabine (GEM), an antimetabolite that terminates DNA synthesis, is commonly used in the treatment of cancers including lung adenocarcinoma (LUAD). However, downregulation of sensitivity limits the therapeutic effect. Ferroptosis as the new form of regulated cell death has been shown to have great potential for cancer treatment with chemoresistance. Here, three genes with both ferroptosis and GEM-response-associated features were screened from RNA sequencing and public data for constructing an independent risk model. LUAD patients with different risk scores had differences in mutational landscape, gene enrichment pathways, and drug sensitivity. By Cell Counting Kit-8 assay, flow cytometry, and colony forming assay, we demonstrate that GEM and ferroptosis inducer (FIN) imidazole Ketone Erastin had a synergistic combined anti-proliferative effect on LUAD cells and knockdown of KIF20A (the core gene of our model) further enhanced cell death in vitro by inducing ferroptosis. In conclusion, we identified a link between ferroptosis and GEM response in LUAD cells and developed a robust signature that can effectively classify LUAD patients into subgroups with different overall survival. For LUAD, the combined treatment modality of GEM and FIN is potentially effective and KIF20A may be a new therapeutic target.

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

Cited by 7 publications

References 35 publications

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair

SN-38 Sensitizes BRCA-Proficient Ovarian Cancers to PARP Inhibitors through Inhibiting Homologous Recombination Repair

The mTORC2 signaling network: targets and cross-talks

KIF20A is associated with clinical prognosis and synergistic effect of gemcitabine combined with ferroptosis inducer in lung adenocarcinoma

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