Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

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

Authors

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

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Female
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Male
Mice
Mice, Inbred BALB C
Middle Aged
Molecular Dynamics Simulation
Mutation / genetics
Protein Conformation
Protein Domains / genetics*
Protein Kinase Inhibitors / pharmacology
Receptor, ErbB-2 / antagonists & inhibitors
Receptor, ErbB-2 / genetics*
Receptor, ErbB-2 / metabolism*
Signal Transduction

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
ERBB2 protein, human
Receptor, ErbB-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding