Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy
Autor: | Andrew T. Magis, Xingming Deng, Wei Zhou, Dongkyoo Park, Jun Zhang, Walter J. Curran, Suresh S. Ramalingam, Ke Xu, Gabriel Sica |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Agonist Cancer Research Programmed cell death endocrine system diseases medicine.drug_class Mutant Apoptosis Treatment of lung cancer Biology medicine.disease_cause NSCLC lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine medicine KRAS Autophagy Lung cancer neoplasms Cell growth Research medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens digestive system diseases 3. Good health respiratory tract diseases 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Molecular Medicine Therapy |
Zdroj: | Molecular Cancer, Vol 18, Iss 1, Pp 1-16 (2019) Molecular Cancer |
ISSN: | 1476-4598 |
Popis: | 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. Electronic supplementary material The online version of this article (10.1186/s12943-019-1012-4) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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