1. Academic Validation
  2. Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma

Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma

  • Biomed Pharmacother. 2021 Jan;133:110906. doi: 10.1016/j.biopha.2020.110906.
Shanwei Shi 1 Huigen Luo 1 Lihong Wang 1 Hua Li 2 Yujie Liang 1 Juan Xia 1 Zhi Wang 1 Bin Cheng 1 Linfeng Huang 3 Guiqing Liao 4 Baoshan Xu 5
Affiliations

Affiliations

  • 1 Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
  • 2 The Stowers Institute for Medical Research, Kansas City, Missouri, United States.
  • 3 Division of Natural and Applied Sciences, Duke Kunshan University, Kunshan, Jiangsu, China.
  • 4 Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: drliaoguiqing@hotmail.com.
  • 5 Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong Province, China. Electronic address: xubsh3@mail.sysu.edu.cn.
Abstract

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.

Keywords

DNA damage and repair; Mammalian target of rapamycin (mTOR); Oral squamous cell carcinoma (OSCC); RNA polymerase I (RNAPI); Reactive oxygen species (ROS); Ribosomal DNA (rDNA).

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