title: Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma.
abstract: Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in signaling coordination. Alterations in the protein signaling coordination were resolved as early as 2.5 days after treatment, anticipating drug resistance long before it was clinically manifest. Combination therapies were identified that resulted in complete and sustained tumor suppression in vivo. This approach may identify actionable alterations in signal coordination that underlie adaptive resistance, which can be suppressed through combination drug therapy, including non-obvious drug combinations.
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA; Department of Applied Physics and Materials Science, California Institute of Technology, Pasadena, CA 91125, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Young Shik
authors.initials: YS
authors.lastname: Shin
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Matsutani
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Masui
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegami
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Herrmann
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Dazy
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Ding
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Kiwook
authors.initials: K
authors.lastname: Hwang
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Jungwoo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Verona, 37134, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bonetti
authors.affiliation: Celgene Corporation, San Diego, CA 92121, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: pmischel@ucsd.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
authors.affiliation: Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: heath@caltech.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Heath
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gini
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002070:Butadienes / Q000008:administration & dosage; D000069439:Dasatinib / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology; D020869:Gene Expression Profiling; D018773:Genes, erbB-1; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000502:physiology; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000008:administration & dosage; D010750:Phosphoproteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D040901:Proteomics / Q000379:methods*; D011719:Pyrazines / Q000008:administration & dosage; D012641:Selection, Genetic; D015398:Signal Transduction / Q000187:drug effects; D059010:Single-Cell Analysis / Q000379:methods*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D002070:Butadienes; C583190:CC214-2; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009570:Nitriles; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C113580:U 0126; C512478:EGFR protein, human; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D000069439:Dasatinib