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Cancer Cell. 2018 Nov 12;34(5):792-806.e5. doi: 10.1016/j.ccell.2018.09.010. Epub 2018 Oct 25.

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

Author information

1
Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA.
2
Tata Memorial Hospital, Parel, Mumbai 400012, India.
3
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA.
4
Molecular Oncology Department, Genentech Inc., South San Francisco, CA 94080, USA.
5
Department of Molecular Biology, SciGenom Labs, Cochin, Kerala 682037, India.
6
Research Division, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India.
7
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
8
Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA; Bioinformatics and Computational Biology Department, Genentech Inc., South San Francisco, CA 94080, USA.
9
Research and Development Department, MedGenome Inc., Foster City, CA 94404, USA.
10
Bioinformatics Department, MeGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India.
11
Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.
12
Department of Medical Oncology, Christian Medical College and Hospital, Vellore 632004, India.
13
ACTREC, Tata Memorial Centre, Navi Mumbai 410210, India; Homi Bhaba National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India.
14
Pathology Department, Genentech Inc., South San Francisco, CA 94080, USA.
15
Division of Thoracic Surgery, The Lung Center and the International Mesothelioma Program, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
16
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.
17
Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: sekar@gene.com.

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.

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

PMID:
30449325
PMCID:
PMC6248889
DOI:
10.1016/j.ccell.2018.09.010
[Indexed for MEDLINE]
Free PMC Article

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