Abstract 3485: Global DNA methylation level is associated with the sensitivity of cytotoxic and senotherapeutic drugs in gastrointestinal tumors

Abstract Background: Gastrointestinal cancer has become a severe burden around the world. Marker-guided treatment and clinical trials with sensitive anti-tumor drugs are critical for improving cancer survival. The decreasing DNA methylation levels of repetitive elements, such as LINE-1 and ALU, have been identified as the common biomarkers in cancer and aging. However, it remains unclear whether the methylation levels of repetitive elements can imply the drug sensitivity in gastrointestinal cancer. We investigated the association of LINE-1 and ALU methylations with the sensitivity of cytotoxic and senotherapeutic drugs in gastric cancer (GC) and colorectal cancer (CRC). Methods: The profiles of DNA methylation and gene expression were obtained from GC and CRC patients from the TCGA cohorts. Then, we calculated the averaging methylation level of two repetitive elements (LINE-1 and ALU) to quantify the global methylation levels by using the probes targeting the repetitive elements in 450K methylation array. The sensitivity of anti-tumor drugs, including the cytotoxic (oxaliplatin and fluorouracil) and five senotherapeutic agents (Dasatinib, Nutlin-3a, Navitoclax, Rapamycin, ABT737), were inferred with Oncopredict R package based on the gene expression profile. The Pearson analysis was conducted to test the correlation between DNA methylation and drug sensitivity. Results: The ALU methylation was associated with the sensitivities of cytotoxic (oxaliplatin: r = 0.171, P = 0.001; fluorouracil: r = 0.158, P = 0.002) and senotherapeutic agents (Dasatinib: r = 0.162, P = 0.002, Nutlin-3a: r = 0.109, P = 0.037, Navitoclax: r = 0.007, P = 0.931, Rapamycin: r = 0.144, P = 0.006, ABT737: r = 0.054, P = 0.523) in GC, while the association of LINE-1 methylation with drug sensitivities was observed in less drugs with weak correlation, including the cytotoxic (oxaliplatin: r = 0.132, P = 0.013; fluorouracil: r = 0.122, P = 0.019) and senotherapeutic agents (Dasatinib: r = 0.129, P = 0.014, Nutlin-3a: r = 0.109, P = 0.037, Rapamycin: r = 0.110, P = 0.034). In CRC, there was no correlation between DNA methylation levels of repetitive elements and drug sensitivity except Dasatinib (ALU: r = -0.107, P = 0.043). Conclusion: DNA methylation of repetitive elements could serve as a biomarker for cytotoxic and senotherapeutic drugs in GC. In addition, our findings suggested the promising value of ALU and LINE-1 methylation-guided chemotherapy with senotherapeutics in GC. Keywords: global DNA methylation, repetitive elements, gastrointestinal cancer, drug sensitivity, senotherapeutics Citation Format: Kaixin Lin, Xiaolin Wang, Yanxin Luo, Huichuan Yu. Global DNA methylation level is associated with the sensitivity of cytotoxic and senotherapeutic drugs in gastrointestinal tumors [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 3485.