Abstract 5079: Comparative proteome analysis for predicting the prognosis of trastuzumab-based therapy

Abstract Trastuzumab, a HER2-targeting antibody, has markedly altered the clinical course of the disease in HER2 + gastric cancer, which is 10-15% of metastatic GC. However, the majority of patients develop resistance within one year of treatment. Therefore, understanding the mechanisms of trastuzumab resistance is urgently needed to overcome trastuzumab resistance. This study explored the characteristics of trastuzumab resistant cell lines through comparative proteome analysis. We previously reported establishment of four trastuzumab resistant cell lines from HER2 amplified GC cell lines by trastuzumab dose-escalation treatment; YCC-33TR, YCC-38TR, NCI-N87TR, and SNU-216TR. Formalin-fixed paraffin-embedded tissue samples were obtained 10 GC patients prior to trastuzumab therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed. For analysis of differentially expressed proteins (DEPs), label-free quantitative proteomic profiling was performed using high-resolution LC-MS system. Gene ontology (GO) and KEGG pathway enrichment analyses were conducted using DAVID database. Consistent with the previous results, we found that HER2 expression in TR cell lines remained as high as parental cell lines, also in proteomic profiling. As a result of proteomic analysis, total 5285 proteins were identified in 4 parental and 4 TR cell lines; 4854 common proteins, while 55 proteins unique to parental cell lines and 58 proteins unique to TR cell lines. Then, we did the hierarchical clustering with these DEPs to identify protein expression patterns. We observed that 129 and 62 proteins were upregulated in parental and TR cell lines, respectively (p<0.05). We identified C5orf51 and CENP-E, poor prognostic factors, were upregulated 200-fold in TR cell lines. Interestingly, we found that HLA-B, ITM2C, and PPP1R3D were highly expressed in TR cell lines and trastuzumab poor responders. In conclusion, we performed comparative proteome analysis in parental and TR cell lines and investigated the corresponding expression change. It may gain further novel insights into the mechanisms of trastuzuamb resistance. Citation Format: Juin Park, Woo Sun Kwon, Sun Kyoung Kang, Tae Soo Kim, Jihyun Hwang, Sang Woo Cho, Kyunggon Kim, Hyun Cheol Chung, Sun Young Rha. Comparative proteome analysis for predicting the prognosis of trastuzumab-based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5079.