Chemoresistance mechanisms in colon cancer: focus on conventional chemotherapy

Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool. The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity) leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for development of chemoresistance and whose targeting might enable design of novel combination strategies to overcome resistance to conventional treatment in CRC.