title: Synthetic Lethality of a Novel Small Molecule Against Mutant KRAS-Expressing Cancer Cells Involves AKT-Dependent ROS Production.
abstract: We recently reported the death-inducing activity of a small-molecule compound, C1, which triggered reactive oxygen species (ROS)-dependent autophagy-associated apoptosis in a variety of human cancer cell lines. In this study, we examine the ability of the compound to specifically target cancer cells harboring mutant KRAS with minimal activity against wild-type (WT) RAS-expressing cells.
  
  
  
  HCT116 cells expressing mutated KRAS are susceptible, while the WT-expressing HT29 cells are resistant. Interestingly, C1 triggers activation of mutant RAS, which results in the downstream phosphorylation and activation of AKT/PKB. Gene knockdown of KRAS or AKT or their pharmacological inhibition resulted in the abrogation of C1-induced ROS production and rescued tumor colony-forming ability. We also made use of HCT116 mutant KRAS knockout (KO) cells, which express only a single WT KRAS allele. Exposure of KO cells to C1 failed to increase mitochondrial ROS and cell death, unlike the parental cells harboring mutant KRAS. Similarly, mutant KRAS-transformed prostate epithelial cells (RWPE-1-RAS) were more sensitive to the ROS-producing and death-inducing effects of C1 than the vector only expressing RWPE-1 cells. An in vivo model of xenograft tumors generated with HCT116 KRAS(WT/MUT) or KRAS(WT/-) cells showed the efficacy of C1 treatment and its ability to affect the relative mitotic index in tumors harboring KRAS mutant.
  
  
  
  These data indicate a synthetic lethal effect against cells carrying mutant KRAS, which could have therapeutic implications given the paucity of KRAS-specific chemotherapeutic strategies. Antioxid. Redox Signal. 24, 781-794.
authors.affiliation: 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Kartini
authors.initials: K
authors.lastname: Iskandar
authors.affiliation: 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Majidah
authors.initials: M
authors.lastname: Rezlan
authors.affiliation: 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Sanjiv Kumar
authors.initials: SK
authors.lastname: Yadav
authors.affiliation: 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Chuan Han Jonathan
authors.initials: CH
authors.lastname: Foo
authors.affiliation: 2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: 3 Genome Institute of Singapore , A*STAR, Singapore, Singapore .
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiang
authors.affiliation: 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|4 Department of Hand and Reconstructive Microsurgery, National University Health System , Singapore, Singapore .
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Bellot
authors.affiliation: 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|5 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore , Singapore, Singapore .|6 National University Cancer Institute, National University Health System , Singapore, Singapore .|7 School of Biomedical Sciences, Curtin University , Perth, Australia .
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D005031:Ethylenethiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020125:Mutation, Missense; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D017382:Reactive Oxygen Species; C089291:merodantoin; D005031:Ethylenethiourea; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)