CRISPR-Cas9 Screen Points to Potential Vulnerabilities in KRAS-Mutated Colorectal Cancer

NEW YORK (GenomeWeb) – A team from the University of California, San Diego has uncovered potential vulnerabilities in KRAS-mutated colorectal cancer (CRC) using a CRISPR-Cas9 gene editing screen.

In a study published online today in Cancer Research, UCSD researchers systematically knocked out gene function across the genome in a tumor xenograft model of human CRC and in human CRC cell lines with or without KRAS mutations. In the CRCs containing KRAS mutations, they narrowed in on loss-of-function mutations that boosted or diminished CRC cell viability.

In particular, the team found that CRISPR-Cas9-based gene edits altering NAD kinase or ketohexokinase (KHK) metabolic enzymes could staunch KRAS-mutated CRC growth in the tumor xenograft system — an effect that the group subsequently recreated using pharmacologic inhibitors of these genes. In contrast, however, they did not see the same synthetic lethality in the CRC cell lines, suggesting that the in vivo gene editing method may pick up cancer contributors missed with strictly cell-based screening approaches.

“[T]he metabolic dependencies of tumor cells growing in a laboratory dish may differ dramatically compared to the same cells growing in a living system, underscoring potential limitations of standard laboratory-based cancer cell growth tests,” senior author Tariq Rana, a

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