title: ATM Expression Predicts Veliparib and Irinotecan Sensitivity in Gastric Cancer by Mediating P53-Independent Regulation of Cell Cycle and Apoptosis.
abstract: Identification of synthetically lethal cellular targets and synergistic drug combinations is important in cancer chemotherapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signaling and cell-cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its implications as a predictive biomarker for cancer chemotherapy remain unexplored. The present study evaluated ATM-induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, veliparib (ABT-888) and irinotecan (CPT-11), respectively. ATM expression was detected in a panel of gastric cell lines, and the IC50against each inhibitors was determined. The combinatorial effect of ABT-888 and CPT-11 in gastric cancer cells was also determined both in vitro and in vivo ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy; however, they showed a higher therapeutic effect with ABT-888 and CPT-11 combinatorial therapy. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell-cycle progression and apoptosis in a P53-independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cells to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM-dependent regulation of cellular processes. Mol Cancer Ther; 15(12); 3087-96. ©2016 AACR.
authors.affiliation: Cancer Science Institute of Singapore, Yong loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Vinod Vijay
authors.initials: VV
authors.lastname: Subhash
authors.affiliation: Department of Haematology-Oncology, National University Hospital, Singapore.
authors.forename: Shi Hui
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Department of Haematology-Oncology, National University Hospital, Singapore.
authors.forename: Mei Shi
authors.initials: MS
authors.lastname: Yeo
authors.affiliation: Department of Haematology-Oncology, National University Hospital, Singapore.
authors.forename: Fui Leng
authors.initials: FL
authors.lastname: Yan
authors.affiliation: Cancer Science Institute of Singapore, Yong loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Praveen C
authors.initials: PC
authors.lastname: Peethala
authors.affiliation: Department of Haematology-Oncology, National University Hospital, Singapore.
authors.forename: Natalia
authors.initials: N
authors.lastname: Liem
authors.affiliation: Cancer Science Institute of Singapore, Yong loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Cancer Science Institute of Singapore, Yong loo Lin School of Medicine, National University of Singapore, Singapore. wei_peng_yong@nuhs.edu.sg.|Department of Haematology-Oncology, National University Hospital, Singapore.
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D001562:Benzimidazoles / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D001562:Benzimidazoles; D006657:Histones; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C521013:veliparib; D000077146:Irinotecan; D064007:Ataxia Telangiectasia Mutated Proteins; D015689:Oncogene Protein p21(ras); D002166:Camptothecin