A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity,Science

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A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity
Science ( IF 44.7 ) Pub Date : 2021-10-01 , DOI: 10.1126/science.abf2911
Danielle L Swaney _{1,

2,

3,

4} , Dana J Ramms _{4,

5,

6} , Zhiyong Wang _{4,

6} , Jisoo Park _{4,

7} , Yusuke Goto _{4,

6} , Margaret Soucheray _{1,

2,

3,

4} , Neil Bhola _{4,

8} , Kyumin Kim _{1,

2,

3,

4} , Fan Zheng _{4,

7} , Yan Zeng _{4,

8} , Michael McGregor _{1,

2,

3,

4} , Kari A Herrington ₉ , Rachel O'Keefe _{4,

8} , Nan Jin _{4,

8} , Nathan K VanLandingham _{4,

8} , Helene Foussard _{1,

2,

3,

4} , John Von Dollen _{1,

2,

3,

4} , Mehdi Bouhaddou _{1,

2,

3,

4} , David Jimenez-Morales _{1,

2,

3,

4} , Kirsten Obernier _{1,

2,

3,

4} , Jason F Kreisberg _{4,

7} , Minkyu Kim _{1,

2,

3,

4} , Daniel E Johnson ₈ , Natalia Jura _{3,

4,

10} , Jennifer R Grandis _{4,

8} , J Silvio Gutkind _{4,

5,

6} , Trey Ideker _{4,

7,

11,

12} , Nevan J Krogan _{1,

2,

3,

4}

Affiliation

Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
J. David Gladstone Institutes, San Francisco, CA, USA.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
The Cancer Cell Map Initiative, San Francisco and La Jolla, CA.
Department of Pharmacology, University of California San Diego, La Jolla, CA.
Moores Cancer Center, University of California San Diego, La Jolla, CA.
Division of Genetics, Department of Medicine, University of California San Diego, La Jolla, CA.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
Department of Biochemistry and Biophysics Center for Advanced Light Microscopy at UCSF, University of California San Francisco, San Francisco, CA, USA.
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
Department of Computer Science, University of California San Diego, La Jolla, CA, USA.

We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of cancer-enriched interactions reveals a previously unidentified association of the fibroblast growth factor receptor tyrosine kinase 3 with Daple, a guanine-nucleotide exchange factor, resulting in activation of Gαi- and p21-activated protein kinase 1/2 to promote cancer cell migration. Additionally, we observe mutation-enriched interactions between the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase and PIK3CA (the alpha catalytic subunit of phosphatidylinositol 3-kinase) that can inform the response to HER3 inhibition in vivo. We anticipate that the application of this framework will be valuable for translating genetic alterations into a molecular and clinical understanding of the underlying biology of many disease areas.

中文翻译：

头颈癌的蛋白质网络图揭示了 PIK3CA 突变药物敏感性

我们概述了通过多维蛋白质-蛋白质相互作用图阐明肿瘤遗传复杂性的框架，并将其应用于增强我们对头颈部鳞状细胞癌的理解。该网络揭示了癌症和非癌细胞状态的 771 种相互作用，包括 WT 和突变蛋白同种型。对富含癌症的相互作用进行优先排序揭示了成纤维细胞生长因子受体酪氨酸激酶 3 与鸟嘌呤核苷酸交换因子 Daple 的先前未知关联，导致 Gαi 和 p21 活化蛋白激酶 1/2 的激活以促进癌细胞迁移. 此外，我们观察到人表皮生长因子受体 3 (HER3) 受体酪氨酸激酶和 PIK3CA（磷脂酰肌醇 3-激酶的 α 催化亚基）之间富含突变的相互作用，可以告知体内对 HER3 抑制的反应。我们预计该框架的应用对于将遗传改变转化为对许多疾病领域的潜在生物学的分子和临床理解将是有价值的。

更新日期：2021-10-01

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