Receptor Tyrosine Kinases Fall into Distinct Classes Based on Their Inferred Signaling Networks
Name
Lauffenburger_Receptor tyrosine.pdf
Size
1.83 MB
Format
Adobe PDF
Checksum (MD5)
43d5dab2171bb2ad0312f5bba1b064a3
Author(s)
Wagner, Joel Patrick
Wolf-Yadlin, Alejandro
Sevecka, Mark
Grenier, Jennifer K.
Root, David E.
Lauffenburger, Douglas A.
MacBeath, Gavin
Date Issued
July 2013
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Wagner, J. P., A. Wolf-Yadlin, M. Sevecka, J. K. Grenier, D. E. Root, D. A. Lauffenburger, and G. MacBeath. “Receptor Tyrosine Kinases Fall into Distinct Classes Based on Their Inferred Signaling Networks.” Science Signaling 6, no. 284 (July 16, 2013): ra58–ra58.
Version
Author's final manuscript
Abstract
Although many anticancer drugs that target receptor tyrosine kinases (RTKs) provide clinical benefit, their long-term use is limited by resistance that is often attributed to increased abundance or activation of another RTK that compensates for the inhibited receptor. To uncover common and unique features in the signaling networks of RTKs, we measured time-dependent signaling in six isogenic cell lines, each expressing a different RTK as downstream proteins were systematically perturbed by RNA interference. Network models inferred from the data revealed a conserved set of signaling pathways and RTK-specific features that grouped the RTKs into three distinct classes: (i) an EGFR/FGFR1/c-Met class constituting epidermal growth factor receptor, fibroblast growth factor receptor 1, and the hepatocyte growth factor receptor c-Met; (ii) an IGF-1R/NTRK2 class constituting insulin-like growth factor 1 receptor and neurotrophic tyrosine receptor kinase 2; and (iii) a PDGFRβ class constituting platelet-derived growth factor receptor β. Analysis of cancer cell line data showed that many RTKs of the same class were coexpressed and that increased abundance of an RTK or its cognate ligand frequently correlated with resistance to a drug targeting another RTK of the same class. In contrast, abundance of an RTK or ligand of one class generally did not affect sensitivity to a drug targeting an RTK of a different class. Thus, classifying RTKs by their inferred networks and then therapeutically targeting multiple receptors within a class may delay or prevent the onset of resistance.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/scisignal.2003994
