2. Academic Validation
  3. Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer

Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer

  • Am J Cancer Res. 2017 Mar 1;7(3):473-483.
Yuping Yin 1,  Qian Shen 2,  Peng Zhang 3,  Ruikang Tao 4,  Weilong Chang 5,  Ruidong Li 3,  Gengchen Xie 3,  Weizhen Liu 3,  Lihong Zhang 2,  Prabodh Kapoor 6,  Shumei Song 7,  Jaffer Ajani 7,  Gordon B Mills 8,  Jianying Chen 3,  Kaixiong Tao 3,  Guang Peng 9
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei, China; Department of Clinical Cancer Prevention, The University of Texas, MD Anderson Cancer CenterHouston, TX, USA.
  • 2 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
  • 3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
  • 4 Center for Biomolecular Science and Engineering, University of California Santa Cruz Santa Cruz, CA, USA.
  • 5 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou Henan, China.
  • 6 Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler Tyler, TX, USA.
  • 7 Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
  • 8 Department of Systems Biology, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
  • 9 Department of Clinical Cancer Prevention, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
PMID: 28401005
Abstract

Globally, gastric Cancer is the second leading cause of Cancer deaths because of the lack of effective treatments for patients with advanced tumors when curative surgery is not possible. Thus, there is an urgent need to identify molecular targets in gastric Cancer that can be used for developing novel therapies and prolonging patient survival. Checkpoint kinase 1 (Chk1) is a crucial regulator of cell cycle transition in DNA damage response (DDR). In our study, we report that Chk1 plays an important role in promoting gastric Cancer cell survival and growth, which serves as an effective therapeutic target in gastric Cancer. First, Chk1 ablation by small interfering RNA could significantly inhibit cell proliferation and sensitize the effects of ionizing radiation (IR) treatment in both p53 wild type gastric Cancer cell line AGS, and p53 mutant cell line MKN1. Secondly, we tested the Anticancer effects of Chk1 chemical inhibitor LY2606368, which is a novel Chk1/2 targeted drug undergoing clinical trials in many malignant diseases. We found that LY2606368 can induce DNA damage, and remarkably suppress Cancer proliferation and induce Apoptosis in AGS and MKN1 cells. Moreover, we identified that LY2606368 can significantly inhibit homologous recombination (HR) mediated DNA repair and thus showed marked synergistic Anticancer effect in combination with poly (ADP-ribose) polymerase 1 (PARP1) inhibitor BMN673 in both in vitro studies and in vivo experiments using a gastric Cancer PDx model. The synergy between LY2606368 and PARP1 was likely caused by impaired the G2M checkpoint due to LY2606368 treatment, which forced mitotic entry and cell death in the presence of BMN673. In conclusion, we propose that Chk1 is a valued target for gastric Cancer treatment, especially Chk1 Inhibitor combined with PARP Inhibitor may be a more effective therapeutic strategy in gastric Cancer.

Keywords

BMN673; Chk1; DNA damage response; LY2606368; gastric cancer.

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