Mechanisms of Chemotherapy Resistance in Mucinous Colorectal Cancer

Aims: To investigate differences in expression of chemoresistance and cell death mediators between mucinous and non-mucinous CRC. 

Methods: Expression of chemotherapy resistance, cell death signalling and immune checkpoint genes was compared in mucinous and non-mucinous CRC in an open-access genetics database. A meta-analysis was performed measuring tumour response to neoadjuvant chemoradiotherapy according to expression of the fluorouracil target thymidylate synthase and the expression of thymidylate synthase was determined in an in-vitro model of mucinous rectal cancer. Cell death signalling proteins were analysed in mucinous versus non-mucinous cancer in an in-vitro model and in a tumour microarray.  

Results: Significant differences were observed in the expression of chemotherapy resistance genes between mucinous and non-mucinous CRC. SRPK1 was identified as a prognostic marker in rectal cancer. Significantly higher gene expression of immune checkpoints PD-L1 and TIM-3 was observed in mucinous CRC with mucinous status predicting expression of TIM-3. Low expression of the 5-FU target thymidylate synthase was associated with tumour response in a meta-analysis of neoadjuvant chemoradiotherapy for rectal cancer. Amplification of thymidylate synthase in response to fluorouracil was observed in a mucinous rectal cancer cell line. Significant differences in the expression of apoptotic and necroptotic proteins was observed between mucinous and non-mucinous cancer in a rectal cancer microarray and in a cell line model. 

Conclusion: Mucinous CRC is a distinct CRC subtype with molecular characteristics permitting chemotherapy resistance. These findings may inform investigation of targeted treatment in a therapeutically challenging cancer subtype.