title: Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.
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.
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rosenn@mskcc.org litop@mskcc.org.
authors: Piro
authors: P
authors: Lito
authors: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Martha
authors: M
authors: Solomon
authors: Wellspring Biosciences, La Jolla, CA, USA.
authors: Lian-Sheng
authors: LS
authors: Li
authors: Wellspring Biosciences, La Jolla, CA, USA.
authors: Rasmus
authors: R
authors: Hansen
authors: 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.
authors: Neal
authors: N
authors: Rosen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000483:Alleles; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003545:Cysteine / Q000235:genetics; D003565:Cytidine Diphosphate / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005998:Glycine / Q000235:genetics; D006160:Guanosine Triphosphate / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D058990:Molecular Targeted Therapy; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors
chemical_list: C000605991:ARS853; D000970:Antineoplastic Agents; D001384:Azetidines; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D010879:Piperazines; D003565:Cytidine Diphosphate; D006160:Guanosine Triphosphate; D016283:Proto-Oncogene Proteins p21(ras); D003545:Cysteine; D005998:Glycine