Abstract 3483: SIRT7 as a potential therapeutic target for drug resistance in lung adenocarcinoma: Insights from histone modification-related genes

Abstract

Abstract Background: Lung cancer is one of the leading causes of cancer-related deaths worldwide. Understanding the molecular mechanisms underlying its development and progression is crucial for the development of targeted therapies. In recent years, histone modification has emerged as a key player in the epigenetic regulation of gene expression, and its involvement in lung cancer has gained significant attention. Histone modifications, including methylation, acetylation, phosphorylation, and ubiquitination, influence chromatin structure and, consequently, gene transcription. Aberrant histone modifications can lead to dysregulated gene expression patterns, contributing to the initiation and progression of lung cancer. In this study, we investigated the expression patterns of 55 histone modification-related genes and identified an epigenetic tumor regulator as a potential therapeutic target. Methods: We obtained 55 histone modification-related genes from dbHiMo (http://hme.riceblast.snu.ac.kr/). Transcriptomic (n= 576), clinical data (n=706) and survival data (n=641) of lung adenocarcinoma (LUAD) were downloaded from XenaTCGA database (https://xenabrowser.net/). The transcriptomic and IC50 values with 87 lung cancer cell lines and 310 drugs were downloaded from DepMap portal (https://depmap.org/portal/). RNA-seq data of GSE197555 was downloaded from GEO database (https://www.ncbi.nlm.nih.gov/geo/). All statistical analysis was performed using R. Results: Among a total of 55 genes related to histone modifications, 6 genes including KAT2A, SIRT7, CARM1, KDM5B, HDAC1 and PRMT3 were significantly overexpressed in tumor tissues in LUAD transcriptome data from TCGA. Out of these 6 genes, 3 (KAT2A, SIRT7 and CARM1) showed significant differences in survival analysis with disease-free interval in the adjuvant therapy-received TCGA LUAD dataset. All three demonstrated that as their expression levels increased, the prognosis became worse. The expression levels of SIRT7 and KAT2A were highly positively correlated with the IC50 value of trametinib, which is MEK inhibitor. Among these two genes, the expression level of SIRT7 was up-regulated in trametinib-treated group in resistance to MEK inhibitor in the H460 cell line. However, sensitive to MEK inhibitor in A549, the SIRT7 expression level was down-regulated in the trametinib-treated group. Conclusion: The histone modification-related gene SIRT7 was found to be associated with resistance to trametinib. In this study, these findings suggest that SIRT7 may serve as a potential therapeutic target related to drug resistance in combination therapy with dabrafenib and trametinib. Citation Format: Kyoung-Ho Pyo, YoungJoon Park, Gang-Taik Lee, Juwon Ahn, Su-Jin Choi, Qi Kejia, Taeku Lee, Youngtaek Kim, Joon Yeon Hwang, Byoung Chul Cho. SIRT7 as a potential therapeutic target for drug resistance in lung adenocarcinoma: Insights from histone modification-related genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3483.