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

Autor:	Pahuja KB; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Nguyen TT; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Jaiswal BS; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Prabhash K; Tata Memorial Hospital, Parel, Mumbai 400012, India., Thaker TM; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA., Senger K; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Chaudhuri S; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Kljavin NM; Molecular Oncology Department, Genentech Inc., South San Francisco, CA 94080, USA., Antony A; Department of Molecular Biology, SciGenom Labs, Cochin, Kerala 682037, India., Phalke S; Research Division, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India., Kumar P; Research Division, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India., Mravic M; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Stawiski EW; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA; Bioinformatics and Computational Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Vargas D; Research and Development Department, MedGenome Inc., Foster City, CA 94404, USA., Durinck S; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA; Bioinformatics and Computational Biology Department, Genentech Inc., South San Francisco, CA 94080, USA., Gupta R; Bioinformatics Department, MeGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India., Khanna-Gupta A; Research Division, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India., Trabucco SE; Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA., Sokol ES; Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA., Hartmaier RJ; Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA., Singh A; Department of Medical Oncology, Christian Medical College and Hospital, Vellore 632004, India., Chougule A; Tata Memorial Hospital, Parel, Mumbai 400012, India., Trivedi V; Tata Memorial Hospital, Parel, Mumbai 400012, India., Dutt A; ACTREC, Tata Memorial Centre, Navi Mumbai 410210, India; Homi Bhaba National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India., Patil V; Tata Memorial Hospital, Parel, Mumbai 400012, India., Joshi A; Tata Memorial Hospital, Parel, Mumbai 400012, India., Noronha V; Tata Memorial Hospital, Parel, Mumbai 400012, India., Ziai J; Pathology Department, Genentech Inc., South San Francisco, CA 94080, USA., Banavali SD; Tata Memorial Hospital, Parel, Mumbai 400012, India., Ramprasad V; Research Division, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India., DeGrado WF; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA., Bueno R; 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., Jura N; 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., Seshagiri S; Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: sekar@gene.com.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2018 Nov 12; Vol. 34 (5), pp. 792-806.e5. Date of Electronic Publication: 2018 Oct 25.
DOI:	10.1016/j.ccell.2018.09.010
Abstrakt:	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. (Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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