Abstract 3126: A novel biomarker signature in predicting chemoresistance in colorectal cancer: Potential application in chemotherapy

Abstract

Despite advances in the cytotoxic and targeted therapy, resistance to chemotherapy remains one of the greatest challenges in long-term management of metastatic colorectal cancer, which eventually contributes to patient death as tumors accumulate means of evading treatment. We have recently demonstrated that expression of the tight junction protein claudin-1 increases while claudin-7 expression decreases with human colon cancer (CRC) progression and metastasis. Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) are critically implicated in cancer metastasis and chemoresistance. Taking this to account, we performed a computational assessment of 250 patient datasets from two different cancer centers (Vanderbilt and Moffitt) and identified the gene sets whose expression increased proportionally with claudin-1 expression and decreased with claudin-7, and vice versa, and correlated these gene sets it with chemoresistance, EMT and CSC markers. We identified a resulting 23-gene set biomarker signature, out of these gene clusters. Some of the important candidates based on literature and their function in colorectal cancer which we focused on were SLC6A6, PIK3CA, ASAP1, TMEM and E2F2. This signature was then validated using the TCGA database. To further evaluate functional relevance of this biomarker signature, we developed oxaliplatin resistant DLD-1 and HT29 colon cancer cells. The chemoresistance of these cells were confirmed by determining the IC50 values DLD (Parental) (4.5μM) and HT29 (Parental) (10.08 μM), after exposing them to increasing conc. of clinically relevant dose of oxaliplatin DLD (Oxaliplatin-R) (16.35 μM) and HT29 (Oxaliplatin-R) (20.05 μM). To our interest, we observed a significant upregulation of SLC6A6, PIK3CA, ASAP1, TMEM and downregulation of E2F2 in DLDOxaR and HT29OxaR cells compared to parental cells. Moreover, DLDOxaR and HT29OxaR cells possessed significantly increased expression of EMT markers such as α-SMA, vimentin, Snail and Slug along with enrichment of the stem cell markers like CD133, CD44 and Aldh1, colony and sphere forming ability. A concomitant decrease in E-cadherin characterized these cells. A similar increase in the expressions of SLC6A6, PIK3CA, ASAP1, TMEM and decrease in E2F2 was observed in colon cancer mouse models as well as chemoresistant patient samples. Taken together, we propose a new predictive biomarker signature which may offer insights into identifying new therapies required to overcome the acquired resistance of colon cancer towards Oxaliplatin and uncover potential molecular pathways involved in treatment failure to help guide therapeutic alternative. Citation Format: Saiprasad Gowrikumar, Kristina Pravoverov, Caroline Selisteda, Kiran D. Bastola, Steven Chen, Joshua J. Smith, Mary K. Washington, Amar B. Singh, Punita Dhawan. A novel biomarker signature in predicting chemoresistance in colorectal cancer: Potential application in chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3126.