title: Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia.
abstract: Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, includingMLL-AF4andTCF3-HLFALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Viktoras
authors.initials: V
authors.lastname: Frismantas
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Maria Pamela
authors.initials: MP
authors.lastname: Dobay
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Joelle
authors.initials: J
authors.lastname: Tchinda
authors.affiliation: School of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Dunn
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kunz
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Paulina
authors.initials: P
authors.lastname: Richter-Pechanska
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Blerim
authors.initials: B
authors.lastname: Marovca
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Orrin
authors.initials: O
authors.lastname: Pail
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jenni
authors.affiliation: Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, OR.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Timothy J
authors.identifier: 0000-0002-4843-4639
authors.initials: TJ
authors.lastname: Brown
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Collins
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Uhrig
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: Gnana P
authors.initials: GP
authors.lastname: Balasubramanian
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Obul R
authors.initials: OR
authors.lastname: Bandapalli
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Salome
authors.initials: S
authors.lastname: Higi
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Eugster
authors.affiliation: Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Pamela
authors.initials: P
authors.lastname: Voegeli
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.|Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.affiliation: Department of Pediatrics, University of California-San Francisco, San Francisco, CA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: Division of Molecular and Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.|Tata Translational Cancer Research Centre, Tata Medical Centre, Kolkata, India.
authors.forename: Vaskar
authors.initials: V
authors.lastname: Saha
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Irving
authors.affiliation: Division of Pediatric Stem Cell Therapy, Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.affiliation: Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Radimerski
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.|Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Arend
authors.initials: A
authors.lastname: Von Stackelberg
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.|Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.|German Cancer Consortium, Heidelberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Synthetic and Systems Biology Unit, Hungarian Academy of Sciences, Biological Research Center, Szeged, Hungary; and.|Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Horvath
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat C
authors.initials: BC
authors.lastname: Bornhauser
authors.affiliation: Department of Oncology, and.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Jean-Pierre
authors.identifier: 0000-0001-6571-6227
authors.initials: JP
authors.lastname: Bourquin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D064593:Heterografts; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents