Cancer therapeutics: Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism Academic Article uri icon

Overview

MeSH Major

  • Adenocarcinoma
  • Antineoplastic Agents
  • Azetidines
  • Enzyme Inhibitors
  • Lung Neoplasms
  • Piperazines
  • Proto-Oncogene Proteins p21(ras)

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.

publication date

  • February 5, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4955282

Digital Object Identifier (DOI)

  • 10.1126/science.aad6204

PubMed ID

  • 26841430

Additional Document Info

start page

  • 604

end page

  • 8

volume

  • 351

number

  • 6273