Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy.
Animals
Antineoplastic Agents
/ chemistry
Autophagy
/ drug effects
Benzoates
/ chemistry
Binding Sites
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Female
Gene Expression Regulation, Neoplastic
Guanosine Diphosphate
/ chemistry
Guanosine Triphosphate
/ chemistry
Humans
Lung Neoplasms
/ drug therapy
Male
Mice, Nude
Mice, Transgenic
Models, Molecular
Mutation
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Proto-Oncogene Proteins p21(ras)
/ agonists
Signal Transduction
Small Molecule Libraries
/ chemistry
Xenograft Model Antitumor Assays
Agonist
Apoptosis
Autophagy
KRAS
NSCLC
Therapy
Journal
Molecular cancer
ISSN: 1476-4598
Titre abrégé: Mol Cancer
Pays: England
ID NLM: 101147698
Informations de publication
Date de publication:
10 04 2019
10 04 2019
Historique:
received:
04
12
2018
accepted:
25
03
2019
entrez:
12
4
2019
pubmed:
12
4
2019
medline:
20
8
2019
Statut:
epublish
Résumé
Lung cancer patients with KRAS mutation(s) have a poor prognosis due in part to the development of resistance to currently available therapeutic interventions. Development of a new class of anticancer agents that directly targets KRAS may provide a more attractive option for the treatment of KRAS-mutant lung cancer. Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS. In vitro GDP/GTP exchange assay reveals that KRA-533 activates KRAS by preventing the cleavage of GTP into GDP, leading to the accumulation of GTP-KRAS, an active form of KRAS. Treatment of human lung cancer cells with KRA-533 resulted in increased KRAS activity and suppression of cell growth. Lung cancer cell lines with KRAS mutation were relatively more sensitive to KRA-533 than cell lines without KRAS mutation. Mutating one of the hydrogen-bonds among the KRA-533 binding amino acids in KRAS (mutant K117A) resulted in failure of KRAS to bind KRA-533. KRA-533 had no effect on the activity of K117A mutant KRAS, suggesting that KRA-533 binding to K117 is required for KRA-533 to enhance KRAS activity. Intriguingly, KRA-533-mediated KRAS activation not only promoted apoptosis but also autophagic cell death. In mutant KRAS lung cancer xenografts and genetically engineered mutant KRAS-driven lung cancer models, KRA-533 suppressed malignant growth without significant toxicity to normal tissues. The development of this KRAS agonist as a new class of anticancer drug offers a potentially effective strategy for the treatment of lung cancer with KRAS mutation and/or mutant KRAS-driven lung cancer.
Sections du résumé
BACKGROUND
Lung cancer patients with KRAS mutation(s) have a poor prognosis due in part to the development of resistance to currently available therapeutic interventions. Development of a new class of anticancer agents that directly targets KRAS may provide a more attractive option for the treatment of KRAS-mutant lung cancer.
RESULTS
Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS. In vitro GDP/GTP exchange assay reveals that KRA-533 activates KRAS by preventing the cleavage of GTP into GDP, leading to the accumulation of GTP-KRAS, an active form of KRAS. Treatment of human lung cancer cells with KRA-533 resulted in increased KRAS activity and suppression of cell growth. Lung cancer cell lines with KRAS mutation were relatively more sensitive to KRA-533 than cell lines without KRAS mutation. Mutating one of the hydrogen-bonds among the KRA-533 binding amino acids in KRAS (mutant K117A) resulted in failure of KRAS to bind KRA-533. KRA-533 had no effect on the activity of K117A mutant KRAS, suggesting that KRA-533 binding to K117 is required for KRA-533 to enhance KRAS activity. Intriguingly, KRA-533-mediated KRAS activation not only promoted apoptosis but also autophagic cell death. In mutant KRAS lung cancer xenografts and genetically engineered mutant KRAS-driven lung cancer models, KRA-533 suppressed malignant growth without significant toxicity to normal tissues.
CONCLUSIONS
The development of this KRAS agonist as a new class of anticancer drug offers a potentially effective strategy for the treatment of lung cancer with KRAS mutation and/or mutant KRAS-driven lung cancer.
Identifiants
pubmed: 30971271
doi: 10.1186/s12943-019-1012-4
pii: 10.1186/s12943-019-1012-4
pmc: PMC6456974
doi:
Substances chimiques
Antineoplastic Agents
0
Benzoates
0
KRAS protein, human
0
Small Molecule Libraries
0
Guanosine Diphosphate
146-91-8
Guanosine Triphosphate
86-01-1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
85Subventions
Organisme : NCI NIH HHS
ID : P30 CA086862
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136534
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193828
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200905
Pays : United States
Commentaires et corrections
Type : ErratumIn
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