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dc.contributor.authorJia, Yongen_US
dc.contributor.authorYun, Cai-Hongen_US
dc.contributor.authorPark, Eunyoungen_US
dc.contributor.authorErcan, Daliaen_US
dc.contributor.authorManuia, Marien_US
dc.contributor.authorJuarez, Joseen_US
dc.contributor.authorXu, Chunxiaoen_US
dc.contributor.authorRhee, Kevinen_US
dc.contributor.authorChen, Tingen_US
dc.contributor.authorZhang, Haikuoen_US
dc.contributor.authorPalakurthi, Sangeethaen_US
dc.contributor.authorJang, Jaebongen_US
dc.contributor.authorLelais, Geralden_US
dc.contributor.authorDiDonato, Michaelen_US
dc.contributor.authorBursulaya, Badryen_US
dc.contributor.authorMichellys, Pierre-Yvesen_US
dc.contributor.authorEpple, Roberten_US
dc.contributor.authorMarsilje, Thomas H.en_US
dc.contributor.authorMcNeill, Matthewen_US
dc.contributor.authorLu, Wenshuoen_US
dc.contributor.authorHarris, Jenniferen_US
dc.contributor.authorBender, Stevenen_US
dc.contributor.authorWong, Kwok-Kinen_US
dc.contributor.authorJänne, Pasi A.en_US
dc.contributor.authorEck, Michael J.en_US
dc.date.accessioned2016-12-02T15:25:27Z
dc.date.issued2016en_US
dc.identifier.citationJia, Y., C. Yun, E. Park, D. Ercan, M. Manuia, J. Juarez, C. Xu, et al. 2016. “Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors.” Nature 534 (7605): 129-132. doi:10.1038/nature17960. http://dx.doi.org/10.1038/nature17960.en
dc.identifier.issn0028-0836en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:29626153
dc.description.abstractEGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harboring activating mutations in the EGFR kinase1,2, but resistance arises rapidly, most frequently due to the secondary T790M mutation within the ATP-site of the receptor.3,4 Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant5,6, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond7. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternate mechanisms of action. Here we describe rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild type receptor. A crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays, but as a single agent is not effective in blocking EGFR-driven proliferation in cells due to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state8. We observe dramatic synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization9,10, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by L858R/T790M EGFR and by L858R/T790M/C797S EGFR, a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/nature17960en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929832/pdf/en
dash.licenseLAAen_US
dc.titleOvercoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitorsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNatureen
dash.depositing.authorJang, Jaebongen_US
dc.date.available2016-12-02T15:25:27Z
dc.identifier.doi10.1038/nature17960*
dash.authorsorderedfalse
dash.contributor.affiliatedJang, Jaebong
dash.contributor.affiliatedEck, Michael


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