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Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations.

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.

SUBMITTER: Pahuja KB 

PROVIDER: S-EPMC6248889 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations.

Pahuja Kanika Bajaj KB   Nguyen Thong T TT   Jaiswal Bijay S BS   Prabhash Kumar K   Thaker Tarjani M TM   Senger Kate K   Chaudhuri Subhra S   Kljavin Noelyn M NM   Antony Aju A   Phalke Sameer S   Kumar Prasanna P   Mravic Marco M   Stawiski Eric W EW   Vargas Derek D   Durinck Steffen S   Gupta Ravi R   Khanna-Gupta Arati A   Trabucco Sally E SE   Sokol Ethan S ES   Hartmaier Ryan J RJ   Singh Ashish A   Chougule Anuradha A   Trivedi Vaishakhi V   Dutt Amit A   Patil Vijay V   Joshi Amit A   Noronha Vanita V   Ziai James J   Banavali Sripad D SD   Ramprasad Vedam V   DeGrado William F WF   Bueno Raphael R   Jura Natalia N   Seshagiri Somasekar S  

Cancer cell 20181025 5

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 stabilizin  ...[more]

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