An Unbiased Functional Genetics Screen Identifies Rare Activating ERBB4 Mutations.

Autor:	Chakroborty D; Institute of Biomedicine, University of Turku, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Turku Doctoral Programme of Molecular Medicine, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Ojala VK; Institute of Biomedicine, University of Turku, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Turku Doctoral Programme of Molecular Medicine, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Knittle AM; Institute of Biomedicine, University of Turku, Turku, Finland., Drexler J; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Tamirat MZ; Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.; InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland.; Graduate School of Åbo Akademi University (Informational and Structural Biology Doctoral Network), Turku, Finland., Ruzicka R; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Bosch K; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Woertl J; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Schmittner S; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Elo LL; Institute of Biomedicine, University of Turku, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Johnson MS; Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland.; InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland., Kurppa KJ; Institute of Biomedicine, University of Turku, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland., Solca F; Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria., Elenius K; Institute of Biomedicine, University of Turku, Turku, Finland.; Medicity Research Laboratories, University of Turku, Turku, Finland.; Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.; Department of Oncology, Turku University Hospital, Turku, Finland.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 Jan 07; Vol. 2 (1), pp. 10-27. Date of Electronic Publication: 2022 Jan 07 (Print Publication: 2022).
DOI:	10.1158/2767-9764.CRC-21-0021
Abstrakt:	Despite the relatively high frequency of somatic ERBB4 mutations in various cancer types, only a few activating ERBB4 mutations have been characterized, primarily due to lack of mutational hotspots in the ERBB4 gene. Here, we utilized our previously published pipeline, an in vitro screen for activating mutations, to perform an unbiased functional screen to identify potential activating ERBB4 mutations from a randomly mutated ERBB4 expression library. Ten potentially activating ERBB4 mutations were identified and subjected to validation by functional and structural analyses. Two of the 10 ERBB4 mutants, E715K and R687K, demonstrated hyperactivity in all tested cell models and promoted cellular growth under two-dimensional and three-dimensional culture conditions. ERBB4 E715K also promoted tumor growth in in vivo Ba/F3 cell mouse allografts. Importantly, all tested ERBB4 mutants were sensitive to the pan-ERBB tyrosine kinase inhibitors afatinib, neratinib, and dacomitinib. Our data indicate that rare ERBB4 mutations are potential candidates for ERBB4-targeted therapy with pan-ERBB inhibitors. Statement of Significance: ERBB4 is a member of the ERBB family of oncogenes that is frequently mutated in different cancer types but the functional impact of its somatic mutations remains unknown. Here, we have analyzed the function of over 8,000 randomly mutated ERBB4 variants in an unbiased functional genetics screen. The data indicate the presence of rare activating ERBB4 mutations in cancer, with potential to be targeted with clinically approved pan-ERBB inhibitors. Competing Interests: D. Chakroborty reports grants from University of Turku Graduate School, K. Albin Johansson Foundation, and Juhani Aho Foundation for Medical Research during the conduct of the study; non-financial support from Finnish Cancer Foundation outside the submitted work. V.K. Ojala reports personal fees from Boehringer Ingelheim and grants from Finnish Cultural Foundation during the conduct of the study. A.M. Knittle reports grants from Boehringer Ingelheim during the conduct of the study; other from Merck Sharp & Dohme outside the submitted work. J. Drexler reports Boehringer-Ingelheim RCV Employment. M.Z. Tamirat reports grants from The Magnus Ehrnrooth Foundation, The Maud Kuistila Memorial Foundation, grants from The Orion Research Foundation, and grants from K. Albin Johansson Foundation during the conduct of the study. R. Ruzicka reports Boehringer-Ingelheim RCV Employment. K. Bosch reports Boehringer-Ingelheim RCV Empoyment. J. Woertl reports Boehringer-Ingelheim RCV Employment. S. Schmittner reports Boehringer Ingelheim RCV Employment. M.S. Johnson reports grants from Sigrid Juselius Foundation and Academy of Finland during the conduct of the study; grants from Academy of Finland outside the submitted work. F. Solca reports a patent to WO 02/50043 A1 issued; and Boehringer Ingelheim RCV employment. The patent relates to the discovery of several quinazoline derivatives for the treatment of diseases, especially tumoral diseases and includes afatinib which was used in this publication. There is no new patent application based on the work presented in this article. K. Elenius reports grants from Academy of Finland, Cancer Foundation of Finland, Turku University Central Hospital, Boehringer Ingelheim, and Puma Biotechnology during the conduct of the study; other from Roche, Orion, Abomics, and Novo Nordisk outside the submitted work. No other disclosures were reported. (© 2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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