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Science. 2016 Feb 5;351(6273):604-8. doi: 10.1126/science.aad6204. Epub 2016 Jan 14.

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.

Author information

1
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org litop@mskcc.org.
2
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Wellspring Biosciences, La Jolla, CA, USA.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org litop@mskcc.org.

Abstract

It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine 5'-diphosphate-bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRAS(G12C) signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRAS(G12C) is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRAS(G12C) inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRAS(G12C) undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRAS(G12C)-driven cancers.

PMID:
26841430
PMCID:
PMC4955282
DOI:
10.1126/science.aad6204
[Indexed for MEDLINE]
Free PMC Article

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