Journal
CANCER CELL
Volume 34, Issue 5, Pages 792-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.09.010
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Funding
- National Institute of General Medical Sciences [R35 GM122603, R01 GM117593, R01 GM109176]
- Susan G. Komen Foundation Career Award [CCR14299947]
- National Cancer Institute [F32 CA216928]
- HHMI Gilliam Fellowship
- UCSF Discovery Fellowship
- NATIONAL CANCER INSTITUTE [F32CA216928] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM117593, R35GM122603, R01GM109176] Funding Source: NIH RePORTER
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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 patientderived 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.
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