Abstract 2620: Aquaporin 11 as a new predictive biomarker of overall survival and platinum-based chemotherapy response in lung adenocarcinoma patients

Abstract

Abstract Background: Biomarkers predictive of response to chemotherapy are critically needed for the precise selection of treatment protocols in lung adenocarcinoma (LUAD). Aquaporins (AQPs), transmembrane water channels, are emerging targets in cancer. Recently discovered, non-ubiquitous family member aquaporin 11 (AQP11), a tissue-specific endoplasmic reticulum (ER) resident, was identified as a cellular pro-survival factor implicated in the maintenance of ER homeostasis. AQP11 is mapped to 11q13-q14 amplicon harboring oncogenic drivers and associated with poor prognosis in cancer patients. We recently showed that high AQP11 expression is an in-vitro therapeutic biomarker of cisplatin therapy, which directly interferes with AQP11 functional structure. In addition, silencing of AQP11 expression in human lung cancer cell lines significantly increased response to cisplatin treatment. We hypothesized that LUAD tumors expressing high levels of AQP11 depend on AQP11-mediated cytoprotection and would be more responsive to platinum-based chemotherapy targeting AQP11. Method: We downloaded and curated matched mRNA expression, survival, and drug response data from The Cancer Genome Atlas (TCGA) LUAD dataset (N=369). Results: Analysis of PRECOG and TCGA databases showed that high AQP11 mRNA expression is negatively prognostic in patients with LUAD. TCGA LUAD cases were categorized by AQP11 mRNA levels into high and low expression (high = AQP11 mRNA expression mean + 1 standard deviation). Patients with high tumor AQP11 mRNA expression (10.3%) had significantly worse overall survival (OS) compared to patients with low AQP11 expression (p=0.0015). An analysis of patients treated with platinum-based chemotherapy (N=74) showed that patients with high AQP11 mRNA expression (7%) had significantly higher OS then patients with LUAD expressing low levels of AQP11 (p=0.0263). Conclusions: This study identifies AQP11 as a new biomarker of OS and chemotherapy in LUAD patients. It is conceivable that lung tumors expressing high levels of AQP11 are dependent on its function and elevated AQP11 expression renders tumor resistance to microenvironment and therapy-induced stress and associates with lower OS of patients. At the same time, as cisplatin efficiently targets AQP11 functional multimeric structure, these AQP11-depending tumors are more prone to platinum based chemotherapy. This study provides a rationale for combination anti-AQP11 and chemotherapy in LUAD tumors with high AQP11 expression. Citation Format: Michael Sharpnack, David P. Carbone, Mikhail M. Dikov, Elena E. Tchekneva. Aquaporin 11 as a new predictive biomarker of overall survival and platinum-based chemotherapy response in lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2620.