Abstract 5961: NRF2-responsive kinases in esophageal squamous cell carcinoma

Abstract

Abstract Esophageal squamous cell carcinoma (ESCC) ranks as the 7th most frequently diagnosed cancer and the 6th leading cause of cancer-related death worldwide. NRF2 is identified as a therapeutic target for human ESCC, with a mutation rate of approximately 10-22%. Hyperactive NRF2 promotes proliferation, metastasis, and resistance to radiation and chemotherapy in ESCC. Although some evidence suggest NRF2 regulates kinases which contribute to these phenotypes, it remains unclear which kinases are responsive to hyperactive NRF2. Using NRF2 ChIP-seq analysis, we have enrichment of 42 kinases including Akt2 and Pkm and 31 phosphatases including Pten and Dusp16 enriched in the Keap1-/- mouse esophagus in comparison with the wild-type esophagus. We further confirmed the binding of NRF2 to the promoter regions of mouse Akt2 and Pten. mRNA expression profiling revealed enrichement of the PI3K/AKT, RAS, ERK, and GSK3 pathways in the Keap1-/- esophagus as compared to the Nrf2-/-;Keap1-/- esophagus. Immunohistochemical staining showed that pAKT, p-mTOR, pS6, PKM2 were overexpressed in the Keap1-/- esophagus, as well as in the adult NRF2-hyperactive esophagus (Sox2CreER;LSL-Nrf2E79Q/+). Using PhosphoExplorer array and PamChip array to analyze NRF2W24C-KYSE70 cells (in comparison with NRF2null-KYSE70 cells) and Sox2CreER;LSL-Nrf2E79Q/+ mouse esophageal epithelium in comparison with wild-type mouse tissue, we further identified multiple kinases including PI3K as potential NRF2-responsive kinases. These findings suggest a potential role for kinases such as PI3K in NRF2-driven ESCC, and support the idea of targeting both NRF2 and NRF2-responsive kinases as a therapeutic strategy for ESCC. Citation Format: Boopathi Subramaniyan, Zhaohui Xiong, Chorlada Paiboonrungruang, Yahui Li, M Ben Major, Xiaoxin Chen. NRF2-responsive kinases in esophageal squamous cell carcinoma [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 5961.