CRISPR-Cas9 technique helps identify drug targets for KRAS-mutated cancer

A study, funded in part by the National Institutes of Health and led by the University of California San Diego School of Medicine, has identified genes affecting the growth of KRAS-mutated colorectal cancer cell lines in mice. Described in the journal Cancer Research on 27 September 2017, the study points to a number of therapeutic targets for KRAS-mutated tumors.

The protein encoded by the KRAS gene plays key roles in regulating cell division. The KRAS gene belongs to the RAS family of oncogenes, which are frequently mutated in human cancer. Approximately one-fifth of all human cancers involve mutations in KRAS. So KRAS has been suggested as a potential target for cancer treatment. Unfortunately, attempts to directly target KRAS have proved unsuccessful.

To identify new therapeutic targets for KRAS-mutated cancer, scientists try another approach, known as the synthetic lethal approach. Synthetic lethality describes a phenomenon that a combination of two or more defects leads to cell death while one defect does not.

In this work, the researchers investigated synthetic lethal genetic interactions in colorectal cancer. Using CRISPR-Cas9, the researchers systematically inactivated every gene in human colorectal cancer cells harboring mutant KRAS or wild-type KRAS. Next, the researchers examined the growth of these cancer cells in mice. The observations showed that inactivation of the NADK and KHK genes significantly decreased the growth of KRAS-mutated cancer cells in mice. No such association was found in normal KRAS cancer cells.

Taken together, the data suggest that NADK and KHK, which both encode metabolic enzymes, are candidate KRAS synthetic lethal genes.

To verify the findings, the researchers evaluated the effect of small molecule inhibitors of NADK and KHK on tumor growth. Likewise, NADK and KHK inhibitors reduced the growth of KRAS-mutated cancer cells in mice, but not normal KRAS cancer cells. This confirmed that both NADK and KHK are critical for the growth of KRAS-mutated cancer in vivo.

Notably, in vitro experiments using cultured cancer cells did not yield the same results as the above experiments. This may be due to the remarkable differences between cancer cells growing in the lab and cancer cells growing in living animals, explained the first author Dr. Tariq Rana from the University of California San Diego.

Additionally, the study also identified novel tumor suppressor genes in the context of mutant KRAS.

Collectively, the study highlights the importance of CRISPR-Cas9 in discovering therapeutic targets and suggests NADK and KHK as new gene targets for KRAS-mutated cancer.
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