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Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors
Yong Jia, Cai-Hong Yun, Eunyoung Park, Dalia Ercan, Mari Manuia, Jose Juarez, Chunxiao Xu, Kevin Rhee, Ting Chen, Haikuo Zhang, Sangeetha Palakurthi, Jaebong Jang, Gerald Lelais, Michael DiDonato, Badry Bursulaya, Pierre-Yves Michellys, Robert Epple, Thomas H. Marsilje, Matthew McNeill, Wenshuo Lu, Jennifer Harris, Steven Bender, Kwok-Kin Wong, Pasi A. Jänne & Michael J. Eck
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Nature 534, 129–132 (02 June 2016) doi:10.1038/nature17960
Received 15 October 2015 Accepted 29 March 2016 Published online 25 May 2016
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The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase1, 2, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor3, 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 alternative mechanisms of action. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. The 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. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state8. We observe marked 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 EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), 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.
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