Investigating the molecular basis of oxaliplatin resistance in colorectal cancer (CRC) via genome-scale CRISPR screens

Authors

• NR Pawar
• HM Wade
• RW Robey
• MM Gottesman

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer deaths, with a five-year survival rate of 65%. Oxaliplatin, developed as a derivative of the DNA-damaging agent cisplatin, is used as an adjuvant therapy for advanced CRC, yet 90% of patients develop resistance. Several mechanisms of oxaliplatin resistance have been proposed, but few are widely accepted. Genome-wide CRISPR activation and knockout screens were conducted to identify genetic changes that confer resistance to oxaliplatin in two CRC cell lines with distinct molecular backgrounds (SW620 and RKO). Guide RNA libraries covering ~18,000 human genes were utilized to identify several potential mechanisms of resistance. Guide RNAs corresponding to SLC43A1 (LAT3) were the most significantly enriched in knockout screens and depleted in activation screens, suggesting a potential role for the amino acid transporter LAT3 in oxaliplatin resistance. In vitro CRISPR knockout and overexpression of LAT3 in SW620 and RKO cell lines confirm increased resistance or sensitivity to oxaliplatin, respectively, and this correlated with levels of intracellular accumulation of oxaliplatin. Further studies to investigate the specificity of this mechanism of resistance to oxaliplatin in CRC and other cancers are ongoing to clarify the molecular basis of oxaliplatin resistance and uncover potential targeted therapeutic strategies for advanced CRC.

Scientific Focus Area: Cancer Biology

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