Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy
Authors: Wei Zhou
Gabriel L Sica
Dongkyoo Park
Andrew T Magis
Jun Zhang
Ke Xu
Suresh S Ramalingam
Walter J Curran
Xingming Deng
Journal: Molecular Cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Agonist; Apoptosis; Autophagy; KRAS; NSCLC
Affiliations: Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA., Institute for Systems Biology, Seattle, WA, 98109, USA., Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA., Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA., Department of Pathology and Laboratory Medicine, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA., Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Figure 1C appears to have a repeated image. *** Close up ![file] *** Full figure ![file] , 
 I already contacted the first author to fix this mistake. Thank you your excellent catching. , 
 After I contacted first author Dr. Ke Xu, he provided me the corrected Figure 1 as attached. Thank you so much for your valuable comments for this paper.![file] , 
 As corresponding author, I have provided corrected Figure 1 as above. I will contact the Journal to match this correction. This correction does not change any conclusions made in the article. We apologize for this error and any confusion it may have caused. , 
 From corresponding author: The correction has been made and published. See detail via link below: https: molecular-cancer.biomedcentral.com articles 10.1186 s12943-020-01214-5 This correction does not change any conclusions made in the article. The authors apologize for this error and any confusion it may have caused. , 
 #5 Thank you for making the correction and following up here. ,