2. Academic Validation
  3. SHP2-Mediated Inhibition of DNA Repair Contributes to cGAS-STING Activation and Chemotherapeutic Sensitivity in Colon Cancer

SHP2-Mediated Inhibition of DNA Repair Contributes to cGAS-STING Activation and Chemotherapeutic Sensitivity in Colon Cancer

  • Cancer Res. 2021 Jun 15;81(12):3215-3228. doi: 10.1158/0008-5472.CAN-20-3738.
Bin Wei  # 1 2,  Lingyan Xu  # 1,  Wenjie Guo  # 3,  Yuanyuan Wang 1,  Jingjing Wu 2,  Xiaofei Li 1,  Xiaomin Cai 1,  Jinbo Hu 3,  Meijing Wang 3,  Qiang Xu 3,  Wen Liu 4,  Yanhong Gu 5
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
  • 2 Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, P.R. China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, P.R. China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, P.R. China. guyhphd@163.com liuwen1849@126.com.
  • 5 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China. guyhphd@163.com liuwen1849@126.com.
  • # Contributed equally.
PMID: 33820798 DOI: 10.1158/0008-5472.CAN-20-3738
Abstract

As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase-stimulator of IFN genes (STING) pathway plays an important role in antitumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell-intrinsic STING pathway activity and DNA repair in colon Cancer. SHP2 interacted with and dephosphorylated PARP1 after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon Cancer models, in part via STING pathway-mediated antitumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon Cancer. SIGNIFICANCE: Dephosphorylation of PARP1 by SHP2 simultaneously suppresses DNA repair and enhances STING pathway-mediated antitumor immunity, highlighting SHP2 activation as a potential therapeutic approach in colon Cancer.

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