Functional Genomic Screens to Identify Drivers of Chemoresistance
Patients with late-stage colorectal cancer (CRC), especially metastatic CRC, have poor survival rates compared with their early-stage counterparts. This is partly due to the development of resistance to chemotherapy agents – which are used as standard treatment for late-stage CRC. Occurrence of chemoresistance, reduces treatment options and increases the risk of recurrence.
Understanding the molecular mechanisms involved in chemoresistance will enable clinicians and researchers to design strategies to reduce or prevent chemoresistance, reverse chemoresistance after it has occurred, predict chemoresistance potential and finally to design better chemotherapy agents. All these benefits will ultimately increase survival rates.
This project aims to create a comprehensive catalog of genes that are involved in conferring chemoresistance in CRC which will enable us to describe the biological interactions and pathways that enable tumor cells to resist chemotherapy.
As a pilot project we have carried out a whole genome CRISPR negative selection screen on RKO cells, a CRC cell line which are resistant to Oxaliplatin – a component of both FOLFOX and CapeOx, the two most common chemo treatment regimens. The CRISPR screen was conducted in such a way that it would disrupt all the genes in the genome, one gene per clone. If this disrupted gene is essential for chemoresistance, the clone would have been removed from the population. By looking at the genes which have thus been “selected out”, we hope to identify potential genes that are critical mediators chemoresistance.