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Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) is the major cause of morbidity and mortality in head and neck cancer patients worldwide. This malignant disease is challenging to treat because of the lack of effective curative strategies and the high incidence of recurrence. This study aimed to investigate the efficacy of a single and dual approach targeting ribosome biogenesis and protein translation to treat OSCC associated with the copy number variation (CNV) of ribosomal DNA (rDNA). Here, we found that primary OSCC tumors frequently exhibited a partial loss of 45S rDNA copy number and demonstrated a high susceptibility to CX5461 (a selective inhibitor of RNA polymerase I) and the coadministration of CX5461 and INK128 (a potent inhibitor of mTORC1/2). Combined treatment displayed the promising synergistic effects that induced cell apoptosis and reactive oxygen species (ROS) generation, and inhibited cell growth and proliferation. Moreover, INK128 compromised NHEJ-DNA repair pathway to reinforce the antitumor activity of CX5461. In vivo, the cotreatment synergistically suppressed tumor growth, triggered apoptosis and strikingly extended the survival time of tumor-bearing mice. Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.
Duke Scholars
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Related Subject Headings
- Xenograft Model Antitumor Assays
- Squamous Cell Carcinoma of Head and Neck
- Signal Transduction
- Reactive Oxygen Species
- RNA Polymerase I
- Pyrimidines
- Protein Kinase Inhibitors
- Oncology & Carcinogenesis
- Naphthyridines
- Mouth Neoplasms
Citation
![Journal cover image](https://secure.syndetics.com/index.aspx?isbn=/lc.gif&issn=1950-6007&client=dukeuniv)
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Start / End Page
Related Subject Headings
- Xenograft Model Antitumor Assays
- Squamous Cell Carcinoma of Head and Neck
- Signal Transduction
- Reactive Oxygen Species
- RNA Polymerase I
- Pyrimidines
- Protein Kinase Inhibitors
- Oncology & Carcinogenesis
- Naphthyridines
- Mouth Neoplasms