title: Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer.
abstract: OBJECTIVE
  Oncogenic mutations in the KRAS/PI3K/AKT pathway are one of the most frequent alterations in cancer. Although PI3K or AKT inhibitors show promising results in clinical trials, drug resistance frequently emerges. We previously revealed Wnt/β-catenin signaling hyperactivation as responsible for such resistance in colorectal cancer. Here we investigate Wnt-mediated resistance in patients treated with PI3K or AKT inhibitors in clinical trials and evaluate the efficacy of a new Wnt/tankyrase inhibitor, NVP-TNKS656, to overcome such resistance.
  
  
  METHODS
  Colorectal cancer patient-derived sphere cultures and mouse tumor xenografts were treated with NVP-TNKS656, in combination with PI3K or AKT inhibitors.We analyzed progression-free survival of patients treated with different PI3K/AKT/mTOR inhibitors in correlation with Wnt/β-catenin pathway activation, oncogenic mutations, clinicopathological traits, and gene expression patterns in 40 colorectal cancer baseline tumors.
  
  
  RESULTS
  Combination with NVP-TNKS656 promoted apoptosis in PI3K or AKT inhibitor-resistant cells with high nuclear β-catenin content. High FOXO3A activity conferred sensitivity to NVP-TNKS656 treatment. Thirteen of 40 patients presented high nuclear β-catenin content and progressed earlier upon PI3K/AKT/mTOR inhibition. Nuclear β-catenin levels predicted drug response, whereas clinicopathologic traits, gene expression profiles, or frequent mutations (KRAS, TP53, or PIK3CA) did not.
  
  
  CONCLUSIONS
  High nuclear β-catenin content independently predicts resistance to PI3K and AKT inhibitors. Combined treatment with a Wnt/tankyrase inhibitor reduces nuclear β-catenin, reverts such resistance, and represses tumor growth. FOXO3A content and activity predicts response to Wnt/β-catenin inhibition and together with β-catenin may be predictive biomarkers of drug response providing a rationale to stratify colorectal cancer patients to be treated with PI3K/AKT/mTOR and Wnt/β-catenin inhibitors.
authors.affiliation: Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Arqués
authors.affiliation: Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Chicote
authors.affiliation: Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Puig
authors.affiliation: Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Stephan P
authors.initials: SP
authors.lastname: Tenbaum
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Argilés
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. Sage Bionetworks, Fred Hutchinson Cancer Research Centre, Seattle, Washington.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Dienstmann
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Caratù
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Matito
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Silberschmidt
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Early Clinical Drug Development Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Stefania
authors.initials: S
authors.lastname: Landolfi
authors.affiliation: Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: General Surgery Service, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Eloy
authors.initials: E
authors.lastname: Espín
authors.affiliation: Department of HBP Surgery and Transplantation, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Charco
authors.affiliation: Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Vivancos
authors.affiliation: Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain. hgpalmer@vhio.net.
authors.forename: Héctor G
authors.initials: HG
authors.lastname: Palmer
mesh_terms: D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D038501:Tankyrases; D051057:Proto-Oncogene Proteins c-akt