| Literature DB >> 30449325 |
Kanika Bajaj Pahuja1, Thong T Nguyen1, Bijay S Jaiswal1, Kumar Prabhash2, Tarjani M Thaker3, Kate Senger1, Subhra Chaudhuri1, Noelyn M Kljavin4, Aju Antony5, Sameer Phalke6, Prasanna Kumar6, Marco Mravic7, Eric W Stawiski8, Derek Vargas9, Steffen Durinck8, Ravi Gupta10, Arati Khanna-Gupta6, Sally E Trabucco11, Ethan S Sokol11, Ryan J Hartmaier11, Ashish Singh12, Anuradha Chougule2, Vaishakhi Trivedi2, Amit Dutt13, Vijay Patil2, Amit Joshi2, Vanita Noronha2, James Ziai14, Sripad D Banavali2, Vedam Ramprasad6, William F DeGrado7, Raphael Bueno15, Natalia Jura16, Somasekar Seshagiri17.
Abstract
Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) that include G660D, R678Q, E693K, and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the TMD/JMD mutations function by improving the active dimer interface or stabilizing an activating conformation. Further, we found that HER2 G660D employed asymmetric kinase dimerization for activation and signaling. Importantly, anti-HER2 antibodies and small-molecule kinase inhibitors blocked the activity of TMD/JMD mutants. Consistent with this, a G660D germline mutant lung cancer patient showed remarkable clinical response to HER2 blockade.Entities:
Keywords: ERBB2 activation; ERBB2 structure; ERBB2/HER2; HER2 germline mutation; HER2 kinase inhibitors; HER2 somatic mutation; anti-HER2 antibodies; juxtamembrane (JMD) domain mutation; transmembrane domain (TMD) mutation
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Year: 2018 PMID： 30449325 PMCID： PMC6248889 DOI： 10.1016/j.ccell.2018.09.010
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743