The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response
Open accessAbstract
Glioblastoma (GBM) is distinguished by a high degree of intratumoral heterogeneity, which extends to the pattern of expression and amplification of receptor tyrosine kinases(RTKs). Although most GBMs harbor RTK amplifications, clinical trials of small-molecule inhibitors targeting individual RTKs have been disappointing to date. Activation of multiple RTKs within individual GBMs provides a theoretical mechanism of resistance; however, the spectrum of functional RTK dependence among tumor cell subpopulations in actual tumors is unknown. We investigated the pattern of heterogeneity of RTK amplification and functional RTK dependence in GBM tumor cell subpopulations. Analysis of The Cancer Genome Atlas GBM dataset identified 34 of 463 cases showing independent focal amplification of two or more RTKs, most commonly platelet-derived growth factor receptor α (PDGFRA) and epidermal growth factor receptor (EGFR). Dual-color fluorescence in situ hybridization was performed on eight samples with EGFR and PDGFRA amplification, revealing distinct tumor cell subpopulations amplified for only one RTK; in all cases these predominated over cells amplified for both. Cell lines derived from coamplified tumors exhibited genotype selection under RTK-targeted ligand stimulation or pharmacologic inhibition in vitro. Simultaneous inhibition of both EGFR and PDGFR was necessary for abrogation of PI3 kinase pathway activity in the mixed population. DNA sequencing of isolated subpopulations establishes a common clonal origin consistent with late or ongoing divergence of RTK genotype. This phenomenon is especially common among tumors with PDGFRA amplification: overall, 43% of PDGFRA-amplified GBM were found to have amplification of EGFR or the hepatocyte growth factor receptor gene (MET) as well.
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Cites
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“4%, 14/33), as did the majority of MET-altered tumors (3/4), reflecting a pattern of intratumoral heterogeneity that has been previously documented by in situ hybridization (Snuderl et al., 2011; Szerlip et al., 2012).”
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Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics
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Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma
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Metadata
- Authors
- Szerlip, N. J., Pedraza, A., Chakravarty, D., Azim, M., McGuire, J., Fang, Y., Ozawa, T., Holland, E. C., Huse, J. T., Jhanwar, S., Leversha, M. A., Mikkelsen, T., & Brennan, C. W.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-02-08
- Volume
- 109
- Issue
- 8
- Pages
- 3041-3046
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2061760261
- Cited by
- 538
- References
- 39
- FWCI
- 24.71
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Szerlip, N. J., Pedraza, A., Chakravarty, D., Azim, M., McGuire, J., Fang, Y., Ozawa, T., Holland, E. C., Huse, J. T., Jhanwar, S., Leversha, M. A., Mikkelsen, T., & Brennan, C. W. (2012). Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1114033109
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