Abstract
Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)‐inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease‐free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2‐dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1‐overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2‐ERCC1 axis is a key determinant of chemoresistance in CRC.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer-associated mortality in Europe and a key public health issue [1]
ZEB2 immunohistochemistry (IHC) and survival analysis were performed on a pilot cohort of 34 consecutive patients who completed FOLFOX regimen after surgical resection of primary CRC
ZEB2 was not detected in normal colonic epithelium whereas 71% (24/34) of the CRC specimens stained positive for nuclear ZEB2 (Fig. 1A)
Summary
Colorectal cancer (CRC) is the second most common cause of cancer-associated mortality in Europe and a key public health issue [1]. Recurrence is the principle cause of mortality, observed in up to 30% at presentation and develop in 50% after curative surgery [2]. The majority of patients with recurrent disease are incurable and experience a median survival of < 3 years [3]. Despite the drive towards personalised care, the only biomarker in standard clinical use is KRAS mutation status which predicts response to EGFR inhibitors such as cetuximab [5]. This example provides proof of principle that a mechanistic understanding of CRC biology can be translated to improved patient outcomes and highlights the pressing requirement for the identification of new predictive biomarkers of therapy response
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