Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy

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.