title: Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer.
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 bothin vitrostudies andin vivoexperiments 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.
authors.affiliation: 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.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Center for Biomolecular Science and Engineering, University of California Santa Cruz Santa Cruz, CA, USA.
authors.forename: Ruikang
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou Henan, China.
authors.forename: Weilong
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Ruidong
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Gengchen
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler Tyler, TX, USA.
authors.forename: Prabodh
authors.initials: P
authors.lastname: Kapoor
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Shumei
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Jaffer
authors.initials: J
authors.lastname: Ajani
authors.affiliation: Department of Systems Biology, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Tao
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas, MD Anderson Cancer Center Houston, TX, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
keywords: BMN673; Chk1; DNA damage response; LY2606368; gastric cancer