title: Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10.
abstract: ONC201/TIC10 is a small-molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway-inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the antiapoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small-molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes, including the multikinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib cotreatment to enhance anticancer responses.
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Joshua E
authors: JE
authors: Allen
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Varun V
authors: VV
authors: Prabhu
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Mala
authors: M
authors: Talekar
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: A Pieter J
authors: AP
authors: van den Heuvel
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Bora
authors: B
authors: Lim
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: David T
authors: DT
authors: Dicker
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania.
authors: Jennifer L
authors: JL
authors: Fritz
authors: Department of Pharmacology, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors: Adam
authors: A
authors: Beck
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania. wafik.eldeiry@gmail.com.
authors: Wafik S
authors: WS
authors: El-Deiry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000502:physiology*; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D056726:Genetic Association Studies; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; C585684:TIC10 compound; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases