Erb-b2 receptor tyrosine kinase 2 (ERBB2) gene amplification is present in a wide variety of human cancers. ERBB2-targeted therapies have been developed and improved the outcome in patients with ERBB2-positive cancers. Recently, the advent of next-generation sequencing technology has enabled to identify numerous ERBB2 somatic mutations across a variety of cancers, but many of the mutations are still variants of unknown significance (VUS) that await further investigation of clinical relevance. In addition, the sensitivities of those ERBB2 mutations to ERBB2-targeted drugs have not been evaluated systematically. Here we assessed comprehensively the transforming activities as well as drug sensitivities of ERBB2 mutations in a high-throughput manner using the mixed-all-nominated-in-one (MANO) method. We evaluated 55 non-synonymous ERBB2 mutations which are reported recurrently in COSMIC database, and discovered several novel activating mutations which probably drive tumorigenesis. Furthermore, ERBB2 mutations showed varying drug sensitivities to ERBB2-targeted inhibitors. Thus, the MANO method may be a novel approach for assessing VUS, and our findings in this study will be beneficial to deliver personalized medicine to cancer patients harboring ERBB2 mutations.

Citation Format: Masaaki Nagano, Shinji Kohsaka, Toshihide Ueno, Shinya Kojima, Masachika Ikegami, Ikuko Takeda, Hiroyuki Mano. High-throughput functional evaluation of variants of unknown significance in ERBB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 921.