Editors' ChoiceCancer

Putting a chain on mutant KRAS

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Science Translational Medicine  10 Feb 2016:
Vol. 8, Issue 325, pp. 325ec23
DOI: 10.1126/scitranslmed.aaf2010

KRAS, the V-Ki-ras2 Kirsten rat sarcoma viral oncogene, was one of the earliest known human oncogenes. Deeply wired into a range of cellular signalling pathways, mutations in KRAS drive a wide range of human cancer. Oncogenic KRAS mutations occur in three amino acid hotspots, including in glycine 12, which harbours six different mutations in human cancer. These mutations are thought to constitutively activate KRAS function, which makes KRAS an attractive target for the development of inhibitors specific to mutant KRAS. However, despite intense efforts to develop KRAS inhibitors, a clinically effective compound has not been discovered yet.

Now, Patricelli et al. might have made an important step towards finding an effective KRAS inhibitor. Instead of targeting the active form of KRAS G12C, they chose to focus their efforts on locking KRAS in its inactive state. When inactive, a small molecular pocket is exposed in KRAS, situated under a portion of KRAS, which mediates nucleotide exchange and/or GDP/GTP binding (Switch II loop region). Using screening assays and iterative drug design, they identified and optimized compounds that bind to this pocket, resulting in the development of the compound ARS-853. The compound was shown to inhibit KRAS G12C function in cells in vitro at concentrations in the micromolar range compatible with use in humans. The effects of ARS-853 on KRAS signaling and cell growth appeared to be specific to KRAS mutant cells, even at raised concentrations. In addition, mechanistic experiments into the function of ARS-853 revealed an unexpected insight into the biology of mutant KRAS: The KRAS G12C mutation does not seem to constitutively activate KRAS. Rather, its normal turnover between inactive and active state is raised, which would explain why mutant KRAS can exist in an inactive form in the first place.

Although ARS-853 may never make it to the bedside, this study reinforces a creative strategy for targeting mutant KRAS--to lock KRAS in its inactive state. In addition, it has provided a remarkable insight into the mechanism of the KRAS G12C mutation, which seems to send normal KRAS turnover into overdrive.

M. P. Patricelli et al., Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 10.1158/2159-8290.CD-15-1105 (2016). [Abstract]

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