可操作的激活致癌 ERBB2/HER2 跨膜和近膜结构域突变。,Cancer Cell

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可操作的激活致癌 ERBB2/HER2 跨膜和近膜结构域突变。
Cancer Cell ( IF 48.8 ) Pub Date : 2018-Nov-12 , DOI: 10.1016/j.ccell.2018.09.010
Kanika Bajaj Pahuja ₁ , Thong T Nguyen ₁ , Bijay S Jaiswal ₁ , Kumar Prabhash ₂ , Tarjani M Thaker ₃ , Kate Senger ₁ , Subhra Chaudhuri ₁ , Noelyn M Kljavin ₄ , Aju Antony ₅ , Sameer Phalke ₆ , Prasanna Kumar ₆ , Marco Mravic ₇ , Eric W Stawiski ₈ , Derek Vargas ₉ , Steffen Durinck ₈ , Ravi Gupta ₁₀ , Arati Khanna-Gupta ₆ , Sally E Trabucco ₁₁ , Ethan S Sokol ₁₁ , Ryan J Hartmaier ₁₁ , Ashish Singh ₁₂ , Anuradha Chougule ₂ , Vaishakhi Trivedi ₂ , Amit Dutt ₁₃ , Vijay Patil ₂ , Amit Joshi ₂ , Vanita Noronha ₂ , James Ziai ₁₄ , Sripad D Banavali ₂ , Vedam Ramprasad ₆ , William F DeGrado ₇ , Raphael Bueno ₁₅ , Natalia Jura ₁₆ , Somasekar Seshagiri ₁

Affiliation

Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA.
Tata Memorial Hospital, Parel, Mumbai 400012, India.
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA.
Molecular Oncology Department, Genentech Inc., South San Francisco, CA 94080, USA.
Department of Molecular Biology, SciGenom Labs, Cochin, Kerala 682037, India.
Research Division, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
Molecular Biology Department, Genentech Inc., South San Francisco, CA 94080, USA; Bioinformatics and Computational Biology Department, Genentech Inc., South San Francisco, CA 94080, USA.
Research and Development Department, MedGenome Inc., Foster City, CA 94404, USA.
Bioinformatics Department, MeGenome Labs Pvt. Ltd., Bangalore, Karnataka 560099, India.
Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, USA.
Department of Medical Oncology, Christian Medical College and Hospital, Vellore 632004, India.
ACTREC, Tata Memorial Centre, Navi Mumbai 410210, India; Homi Bhaba National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India.
Pathology Department, Genentech Inc., South San Francisco, CA 94080, USA.
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.
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.

解除管制的 HER2 是许多已获批准的抗癌药物的靶标。我们分析了 111,176 名患者肿瘤，并鉴定了 HER2 跨膜结构域 (TMD) 和近膜结构域 (JMD) 的复发突变，包括 G660D、R678Q、E693K 和 Q709L。通过饱和诱变筛选和患者衍生突变测试，我们发现了几种激活 TMD 和 JMD 突变。结构建模和分析表明，TMD/JMD 突变通过改善活性二聚体界面或稳定激活构象发挥作用。此外，我们发现 HER2 G660D 采用不对称激酶二聚化来激活和信号传导。重要的是，抗 HER2 抗体和小分子激酶抑制剂阻断了 TMD/JMD 突变体的活性。与此一致的是，一名 G660D 种系突变肺癌患者对 HER2 阻断表现出显着的临床反应。

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更新日期：2018-10-26

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