Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

Wei Wei; Young Shik Shin; Min Xue; Tomoo Matsutani; Kenta Masui; Huijun Yang; Shiro Ikegami; Yuchao Gu; Ken Herrmann; Dazy Johnson; Xiangming Ding; Kiwook Hwang; Jungwoo Kim; Jian Zhou; Yapeng Su; Xinmin Li; Bruno Bonetti; Rajesh Chopra; C David James; Webster K Cavenee; Timothy F Cloughesy; Paul S Mischel; James R Heath; Beatrice Gini

doi:10.1016/j.ccell.2016.03.012

Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

Cancer Cell. 2016 Apr 11;29(4):563-573. doi: 10.1016/j.ccell.2016.03.012.

Authors

Wei Wei¹, Young Shik Shin², Min Xue³, Tomoo Matsutani⁴, Kenta Masui⁴, Huijun Yang⁴, Shiro Ikegami⁴, Yuchao Gu⁴, Ken Herrmann⁵, Dazy Johnson⁵, Xiangming Ding⁶, Kiwook Hwang³, Jungwoo Kim³, Jian Zhou⁶, Yapeng Su³, Xinmin Li⁶, Bruno Bonetti⁷, Rajesh Chopra⁸, C David James⁹, Webster K Cavenee⁴, Timothy F Cloughesy¹⁰, Paul S Mischel¹¹, James R Heath¹², Beatrice Gini⁴

Affiliations

¹ 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.
² 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.
³ Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA.
⁴ Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Neurological and Movement Sciences, University of Verona, Verona, 37134, Italy.
⁸ Celgene Corporation, San Diego, CA 92121, USA.
⁹ Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹⁰ Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: pmischel@ucsd.edu.
¹² 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Physiological
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Brain Neoplasms / drug therapy
Brain Neoplasms / metabolism*
Brain Neoplasms / pathology
Butadienes / administration & dosage
Dasatinib / administration & dosage
Drug Resistance, Neoplasm
Drug Synergism
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / physiology
Gene Expression Profiling
Genes, erbB-1
Glioblastoma / drug therapy
Glioblastoma / metabolism*
Glioblastoma / pathology
Humans
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice
Models, Biological
Molecular Targeted Therapy*
Multiprotein Complexes / antagonists & inhibitors
Multiprotein Complexes / physiology
Mutation
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Nitriles / administration & dosage
Phosphoproteins / metabolism*
Protein Kinase Inhibitors / therapeutic use*
Proteomics / methods*
Pyrazines / administration & dosage
Selection, Genetic
Signal Transduction / drug effects
Single-Cell Analysis / methods*
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / physiology
Xenograft Model Antitumor Assays

Substances

Butadienes
CC214-2
Multiprotein Complexes
Neoplasm Proteins
Nitriles
Phosphoproteins
Protein Kinase Inhibitors
Pyrazines
U 0126
EGFR protein, human
ErbB Receptors
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
TOR Serine-Threonine Kinases
Dasatinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding