Show simple item record

dc.contributor.authorMeyer, Aaron Samuel
dc.contributor.authorMiller, Miles Aaron
dc.contributor.authorGertler, Frank
dc.contributor.authorLauffenburger, Douglas A.
dc.date.accessioned2014-08-21T16:43:38Z
dc.date.available2014-08-21T16:43:38Z
dc.date.issued2013-08
dc.date.submitted2013-03
dc.identifier.issn1945-0877
dc.identifier.issn1937-9145
dc.identifier.urihttp://hdl.handle.net/1721.1/88954
dc.description.abstractThe relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)–associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor–targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)–elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling.en_US
dc.description.sponsorshipUnited States. Dept. of Defense (Congressionally Directed Medical Research Programs, Breast Cancer Research Program (W81XWH-11-1-0088))en_US
dc.description.sponsorshipNational Science Foundation (U.S.) (Graduate Research Fellowship)en_US
dc.description.sponsorshipRepligen Corporation (Fellowship in Cancer Research)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.). Integrative Cancer Biology Program (1-U54-CA112967)en_US
dc.description.sponsorshipDavid H. Koch Institute for Integrative Cancer Research at MIT (Frontier Research Program Initiator Award)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH R01-CA96504)en_US
dc.language.isoen_US
dc.publisherAmerican Association for the Advancement of Science (AAAS)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1126/scisignal.2004155en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleThe Receptor AXL Diversifies EGFR Signaling and Limits the Response to EGFR-Targeted Inhibitors in Triple-Negative Breast Cancer Cellsen_US
dc.typeArticleen_US
dc.identifier.citationMeyer, A. S., M. A. Miller, F. B. Gertler, and D. A. Lauffenburger. “The Receptor AXL Diversifies EGFR Signaling and Limits the Response to EGFR-Targeted Inhibitors in Triple-Negative Breast Cancer Cells.” Science Signaling 6, no. 287 (August 6, 2013): ra66–ra66.en_US
dc.contributor.departmentDavid H. Koch Institute for Integrative Cancer Research at MITen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorMeyer, Aaron Samuelen_US
dc.contributor.mitauthorMiller, Miles Aaronen_US
dc.contributor.mitauthorGertler, Franken_US
dc.contributor.mitauthorLauffenburger, Douglas A.en_US
dc.relation.journalScience Signalingen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsMeyer, A. S.; Miller, M. A.; Gertler, F. B.; Lauffenburger, D. A.en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-3214-4554
mit.licenseOPEN_ACCESS_POLICYen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record