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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 563-573 |
| Number of pages | 11 |
| Journal | Cancer cell |
| Volume | 29 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 11 2016 |
Funding
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.
ASJC Scopus subject areas
- Oncology
- Cancer Research
