Targeting APE1-Redox Function Reverses SOX9-mediated Chemoresistance in Esophageal Adenocarcinoma.

Gastroesophageal reflux disease is the leading risk factor for esophageal adenocarcinoma (EAC), a malignancy that exhibits marked resistance to chemotherapy and results in poor clinical outcomes. This study aims to define and overcome the mechanisms underlying chemoresistance in EAC to enable the development of novel therapeutic strategies. The study included analysis of RNA sequencing and public datasets. Experimental models consisted of 3-dimensional organotypic cultures, tumorospheres, patient-derived organoids, and de-identified tissue microarrays. In vivo experiments utilized the pL2-IL1β, Krt7CreER;R26rtTA;otet-CDX2, and patient-derived xenograft mouse models. RNA sequencing revealed a significant enrichment of the SRY-Box Transcription Factor 9 (SOX9) molecular signature in patients with EAC. We identified an apurinic/apyrimidinic endonuclease (APE1)-dependent mechanism that activates SOX9 signaling on exposure to acidic bile salts, mimicking reflux conditions. Genetic knockdown or pharmacological inhibition of APE1's redox activity suppressed SOX9 activation under both reflux-mimicking conditions and oxaliplatin treatment. The redox function of APE1 was required to stabilize the SOX9 protein. Immunostaining demonstrated co-overexpression of APE1 and SOX9 in mouse and human EAC lesions, accompanied by Aldehyde Dehydrogenase 1 Family Member A1 expression, a SOX9 transcriptional target implicated in chemotherapeutic resistance. Clinically, patients with high SOX9 signature expression had significantly worse relapse-free survival. Moreover, in vivo treatment with the APE1-redox-specific inhibitor APX2009 enhanced the response of patient-derived xenograft tumors to oxaliplatin by downregulating SOX9. Activation of SOX9 through the APE1-redox function is a key driver of EAC chemoresistance. Targeting APE1's redox activity offers a promising therapeutic strategy to overcome resistance by inhibiting the otherwise "undruggable" SOX9 transcription network.