Related Experiment Video
Updated: Feb 28, 2026
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
RRM1 inhibition sensitizes lung adenocarcinoma to decitabine treatment
Nan Jiang1, Jianyong Liu2, Ajay Vaghasia2
1Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Abstract:
Aberrant DNA methylation has been implicated in tumorigenesis and the development of lung cancer. 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-MS/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.
Insights
Lung cancer cells resist decitabine (DAC) due to high RRM1 levels. Inhibiting RRM1 or ribonucleotide reductase (RNR) boosts DAC efficacy by increasing its DNA incorporation, enhancing tumor suppressor gene activity and STING pathway activation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Aberrant DNA methylation is crucial in lung cancer development.
- Nucleoside analog DNA methyltransferase inhibitors show promise in hematologic malignancies but limited efficacy in solid tumors.
- Mechanisms of primary resistance to these agents in solid tumors remain unclear.
Purpose of the Study:
- To investigate the role of RRM1 in mediating intrinsic resistance to decitabine (DAC) in lung cancer.
- To explore the potential of combining DAC with RNR inhibitors for enhanced lung cancer treatment.
Main Methods:
- Correlation analysis of RRM1 expression and DAC incorporation rates using LC-MS/MS.
- RNA interference-mediated depletion of RRM1 and pharmacological inhibition of RNR.
- Assessment of lung cancer cell survival, xenograft growth, tumor suppressor gene reactivation, and STING pathway activation.
- Measurement of dCTP availability and DAC incorporation into genomic DNA.
Main Results:
- RRM1 expression inversely correlated with DAC incorporation.
- RRM1 or RNR inhibition significantly enhanced DAC's anti-cancer effects in vitro and in vivo.
- RRM1 inhibition increased DAC incorporation by reducing dCTP levels.
- Combined treatment promoted tumor suppressor gene reactivation and STING pathway activation.
Conclusions:
- RRM1/RNR pathway is a key determinant of DAC resistance in lung cancer.
- Combination therapy of DAC with RNR inhibitors represents a promising strategy for lung cancer treatment.
- This approach warrants further clinical investigation and translation.
