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

Wei, Wei and Shin, Young Shik and Xue, Min and Matsutani, Tomoo and Masui, Kenta and Yang, Huijun and Ikegami, Shiro and Gu, Yuchao and Herrmann, Ken and Johnson, Dazy and Ding, Xiangming and Hwang, Kiwook and Kim, Jungwoo and Zhou, Jian and Su, Yapeng and Li, Xinmin and Bonetti, Bruno and Chopra, Rajesh and James, C. David and Cavenee, Webster K. and Cloughesy, Timothy F. and Mischel, Paul S. and Heath, James R. and Gini, Beatrice (2016) Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma. Cancer Cell, 29 (4). pp. 563-573. ISSN 1535-6108. PMCID PMC4831071. http://resolver.caltech.edu/CaltechAUTHORS:20160414-085615562

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.ccell.2016.03.012DOIArticle
http://www.sciencedirect.com/science/article/pii/S1535610816300940PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831071/PubMed CentralArticle
ORCID:
AuthorORCID
Kim, Jungwoo0000-0002-5215-2044
Heath, James R.0000-0001-5356-4385
Additional Information:© 2016 Elsevier B.V. Received: August 2, 2015; Revised: November 25, 2015; Accepted: March 15, 2016; Published: April 11, 2016. This work was supported by the Ben and Catherine Ivy Foundation Fund (J.R.H., P.S.M., and T.F.C.) and by the NIH grants 5U54CA 151819 (W.W., P.S.M., J.R.H.), NS73831 (P.S.M.), the Phelps Family Foundation (W.W., Y.S.S.), and support from the Defeat GBM Research Collaborative, a subsidiary of National Brain Tumor Society (W.K.C., P.S.M., T.F.C.). W.K.C. is a Fellow of the National Foundation for Cancer Research. B.G. received support from The European Commission (PIOF-GA-2010-271819). We thank Dr. David Nathanson for proofreading and comments. W.W., Y.S.S., and B.G. contributed equally to this work. R.C. is employed as vice president at Celgene and has ownership interest. T.F.C. was a consultant and was on the advisory board of Celgene. J.R.H. is a board member of IsoPlexis, which is a company seeking to commercialize the SCBC technology. Accession Numbers: Microarray gene expression and SNP analyses data have been deposited in the Gene Expression Omnibus. The accession numbers are GEO: GSE63387 and GSE53042. WES analysis data have been deposited in the Sequence Read Archive, and the accession number is SRP062496. Author Contributions: W.W., B.G., Y.S.S., P.S.M., and J.R.H. initiated the project and designed the experiments. W.W., B.G., Y.S.S., M.X., X.D., H.Y., T.M., K.M., J.Z., D.J., and S.I. performed the experiments and analyzed the data. B.G. designed and performed the in vivo GBM model. W.W. performed the computational modeling. R.C. supported the CC214-2 tests. T.F.C. contributed to the experiment designs. K.H., K.H., J.K., B.B., Y.S., Y.G., X.L., and C.D.J. supported the experiment realization. W.W., B.G., Y.S.S., W.K.C., P.S.M., and J.R.H. wrote the manuscript.
Funders:
Funding AgencyGrant Number
Ben and Catherine Ivy Foundation FundUNSPECIFIED
NIH5U54CA 151819
NIHNS73831
Phelps Family FoundationUNSPECIFIED
Defeat GBM Research CollaborativeUNSPECIFIED
National Brain Tumor SocietyUNSPECIFIED
National Foundation for Cancer ResearchUNSPECIFIED
European CommissionPIOF-GA-2010-271819
PubMed Central ID:PMC4831071
Record Number:CaltechAUTHORS:20160414-085615562
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160414-085615562
Official Citation: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, Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma, Cancer Cell, Volume 29, Issue 4, 11 April 2016, Pages 563-573, ISSN 1535-6108, http://dx.doi.org/10.1016/j.ccell.2016.03.012. (http://www.sciencedirect.com/science/article/pii/S1535610816300940)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66151
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Apr 2016 16:25
Last Modified:26 Oct 2017 19:38

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