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The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)\u2010inducing 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\u2010free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2\u2010dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the\n                    <jats:italic>ERCC1<\/jats:italic>\n                    gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1\u2010overexpressing CRC cells did not respond to oxaliplatin\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    , 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\u2010ERCC1 axis is a key determinant of chemoresistance in CRC.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.12965","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T03:35:53Z","timestamp":1619840153000},"page":"2065-2083","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["The ZEB2\u2010dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes\n                    <i>ERCC1<\/i>\n                    and\n                    <i>ERCC4<\/i>\n                    in colorectal cancer"],"prefix":"10.1002","volume":"15","author":[{"given":"Rahul","family":"Sreekumar","sequence":"first","affiliation":[{"name":"Cancer Sciences Division University of Southampton 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