Abstract
Background5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets.MethodsPutative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified.ResultsAPRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent withAPRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set. Stratified analysis revealed that protein expression of APRIL in the tumour stroma is associated with survival in adjuvant 5FU treated patients only (n = 103, p < 0.001), and is independently predictive of lack of clinical benefit from adjuvant 5FU [HR 6.25 (95%CI 1.48-26.32), p = 0.013].ConclusionsA combined investigative model, analysing the transcriptional response in clinical tumour specimens and cancers cell lines, has identified APRIL, a novel chemo-resistance biomarker with independent predictive impact in 5FU-treated CRC patients, that may represent a target for novel therapeutics.
Highlights
Significant progress has been made recently in the systemic treatment of colorectal adnocarcinoma (CRC)
Rectal tumour biopsies before and after short course' radiotherapy (SCRT) (n = 4 patients; table 1) were analysed to enable comparison of gene expression changes in patients treated with 5FU-based chemo-radiotherapy with those observed in patients receiving radiotherapy alone
APRIL, a putative 5FU chemo-resistance factor and predictive biomarkerin 5FU treated colorectal cancer patients We examined the relationship between APRIL protein expression and survival after surgical resection
Summary
Significant progress has been made recently in the systemic treatment of colorectal adnocarcinoma (CRC). Older studies with 5FU monotherapy demonstrate that the majority of CRC patients treated will not benefit from 5FU, for example the objective response rate to 5FU or capecitabine monotherapy in advanced CRC is 20% [1]. A predictive biomarker for clinical 5FU resistance would clearly be useful, but progress has been limited in this area and investigation has far failed to fully explain the molecular mechanisms that areimportant for clinical 5FU resistance [2,3,4]. Clinical studies in colorectal cancer, assessing these molecules by a variety of techniques (IHC, RT-PCR, ELISA, genotyping), while demonstrating correlation between benefit (such as response and survival) from 5FU or capecitabine, have so far failed either to demonstrate genuine clinical utility as predictive biomarkers or produce useful targeted agents [3]. Given the widespread clinical use of 5FU or its oral formulations, there is still a need for novel discovery approaches in this area
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