Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma
- Creators
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Wei, Wei
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Shin, Young Shik
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Xue, Min
- Matsutani, Tomoo
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Masui, Kenta
- Yang, Huijun
- Ikegami, Shiro
- Gu, Yuchao
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Herrmann, Ken
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Johnson, Dazy
- Ding, Xiangming
- Hwang, Kiwook
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Kim, Jungwoo
- Zhou, Jian
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Su, Yapeng
- Li, Xinmin
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Bonetti, Bruno
- Chopra, Rajesh
- James, C. David
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Cavenee, Webster K.
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Cloughesy, Timothy F.
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Mischel, Paul S.
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Heath, James R.
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Gini, Beatrice
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.
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.Attached Files
Accepted Version - nihms771139.pdf
Supplemental Material - mmc1.pdf
Supplemental Material - mmc2.xlsx
Supplemental Material - mmc3.xlsx
Supplemental Material - mmc4.xlsx
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Additional details
- Alternative title
- Single cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma
- PMCID
- PMC4831071
- Eprint ID
- 66151
- Resolver ID
- CaltechAUTHORS:20160414-085615562
- Ben and Catherine Ivy Foundation Fund
- NIH
- 5U54CA 151819
- NIH
- NS73831
- Phelps Family Foundation
- Defeat GBM Research Collaborative
- National Brain Tumor Society
- National Foundation for Cancer Research
- European Commission
- PIOF-GA-2010-271819
- Created
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2016-04-14Created from EPrint's datestamp field
- Updated
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2022-05-05Created from EPrint's last_modified field