Abstract 5880: Pan-cancer gene expression analysis of tissue microarray using EdgeSeq Oncology Biomarker Panel and a cross-comparison with ERBB3 immunohistochemical analysis

Abstract

Abstract Background: Antibody-drug conjugate (ADC) is one of the recent break-through approaches of targeting tumors, in which chemotherapeutic agents are attached via linkers to antibodies recognizing membrane proteins on tumor cells and the agents are delivered directly into tumor cells. In ADC drug development, it is important to determine the antibody-target gene expression levels in tumor cells as well as normal tissues. Methods: We characterized an established pan-cancer tissue microarray set by gene expression analysis using HTG EdgeSeq Oncology Biomarker Panel (2,867 genes for 2,376 samples including 17 solid cancer types and 25 normal tissues) and compared it with immunohistochemistry (IHC) result of ERBB3, which is a target of anti-ERBB3 ADC, U3-1402, being investigated in clinical trials. Furthermore, these data were compared with RNA-seq and Reverse-Phase Protein Array (RPPA) publicly available data sets from The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE). Results: Gene signature analyses indicated a similarity of cancer type characteristics between the tissue microarray cohort and TCGA data, such as richness of cancer-associated fibroblast and immune cell infiltrate. As expected, ERBB3 mRNA expression results by EdgeSeq were similar to TCGA RNA-seq data, suggesting an epithelial-biased expression pattern. The result of IHC for ERBB3 showed overall correlation with EdgeSeq mRNA data, such as high IHC scores in melanoma. Interestingly several cancer types and subtypes showed low IHC signals relatively to EdgeSeq data, such as low IHC signals in hepatocellular carcinoma despite of a certain mRNA expression levels. RNA-seq and RPPA data of CCLE did not show such discordance between mRNA and protein levels, which could be a result of the regulation due to in vivo environmental factors. In breast cancer, ERBB3 IHC score levels were generally lower in triple negative breast cancer (TNBC), while TNBC-Mesenchymal subtype showed relatively high IHC score levels comparable to non-TNBC tumor types. In stomach cancer, intestinal subtype showed higher IHC score levels than diffuse subtype despite similar mRNA expression levels. These subtype-specific protein-level regulations were also observed in TCGA RNA-seq and RPPA data comparison. Conclusion: These results suggested a unique protein-level regulation of ERBB3 in tumor cells. It would be important to investigate the significance of protein-level antibody-target expressions on tumor samples, such as IHC on tissue microarray, for antibody-based drug development. Citation Format: Koichiro Inaki, Naoyuki Maeda, Tomoko Shibutani, Serenella Eppenberger-Castori, Stefan Nicolet, Kumiko Koyama, Yui Tanaka, Yuki Kaneda, Kenichi Wakita, Yoshinobu Shiose, Masato Murakami. Pan-cancer gene expression analysis of tissue microarray using EdgeSeq Oncology Biomarker Panel and a cross-comparison with ERBB3 immunohistochemical analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5880.