Journal Article

Augmented antitumor activity by olaparib plus AZD1775 in gastric cancer through disrupting DNA damage repair pathways and DNA damage checkpoint

Lin, Xiaoting, Chen, Dongshao, Li, Zhongwu, Dong, Bin, Zhang, Cheng, Zhang, Xiaotian, Gao, Jing, Shen, Lin

2018

Overview

Background Targeting poly ADP-ribose polymerase (PARP) has been recently identified as a promising option against gastric cancer (GC). However, PARP inhibitors alone achieve limited efficacy. Combination strategies, especially with homologous recombination (HR) impairment, are of great hope to optimize PARP inhibitor’s efficacy and expand target populations but remains largely unknown. Herein, we investigated whether a WEE1/ Polo-like kinase 1 (PLK1) dual inhibitor AZD1775 reported to impair HR augmented anticancer activity of a PARP inhibitor olaparib and its underlying mechanisms. Methods GC cell lines and in vivo xenografts were employed to determine antitumor activity of PARP inhibitor combined with WEE1/PLK1 dual inhibitor AZD1775. Western blot, genetic knockdown by siRNA, flow cytometry, Immunohistochemistry were performed to explore the underlying mechanisms. Results AZD1775 dually targeting WEE1/PLK1 enhanced effects of olaparib on growth inhibition and apoptotic induction in GC cells. Mechanistic investigations elucidate that WEE1/PLK1 blockade downregulated several HR-related proteins and caused an accumulation in γH2AX. As confirmed in both GC cell lines and mice bearing GC xenografts, these effects were enhanced by AZD1775-olaparib combination compared to olaparib alone, suggesting that disrupting HR-mediated DNA damage repairs (DDR) by WEE1/PLK1 blockade might be responsible for improved GC cells’ response to PARP inhibitors. Given the DNA damage checkpoint as a primary target of WEE1 inhibition, our data also demonstrate that AZD1775 abrogated olaparib-activated DNA damage checkpoint through CDC2 de-phosphorylation, followed by mitotic progression with unrepaired DNA damage (marked by increased pHH3-stained and γH2AX-stained cells, respectively). Conclusions PARP inhibitor olaparib combined with WEE1/PLK1 dual inhibitor AZD1775 elicited potentiated anticancer activity through disrupting DDR signaling and the DNA damage checkpoint. It sheds light on the combination strategy of WEE1/PLK1 dual inhibitors with PARP inhibitors in the treatment of GC, even in HR-proficient patients.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antineoplastic Agents - pharmacology / Apoptosis / Apoptosis - drug effects / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer Research / Cancer therapies / Cell cycle / Cell Cycle Proteins - antagonists & inhibitors / Cell Line, Tumor / Cell Proliferation - drug effects / Combination / Complications and side effects / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA damage / DNA Damage - drug effects / DNA damage checkpoint / DNA Repair - drug effects / Dosage and administration / Drug Synergism / Drug therapy / Female / Gastric cancer / Genetic aspects / HR deficiency / Humans / Immunoglobulins / Immunology / Laboratories / Medical prognosis / Mice / Nuclear Proteins - antagonists & inhibitors / Olaparib / Oncology / Pancreatic cancer / PARP inhibitor / Phthalazines - pharmacology / Physiological aspects / Piperazines - pharmacology / Polo-Like Kinase 1 / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Prostate cancer / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - antagonists & inhibitors / Proto-Oncogene Proteins - antagonists & inhibitors / Pyrazoles - pharmacology / Pyrimidines - pharmacology / Pyrimidinones / Rodents / Stomach cancer / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / WEE1/PLK1 dual inhibitor / Xenograft Model Antitumor Assays