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Combined blockade of polo-like kinase and pan-RAF is effective against NRAS-mutant non-small cell lung cancer cells

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Authors
Park, Siyeon; Kim, Tae Min; Cho, Sung-Yup; Kim, Soyeon; Oh, Yumi; Kim, Miso; Keam, Bhumsuk; Kim, Dong-Wan; Heo, Dae Seog
Issue Date
2020-12
Citation
Cancer Letters, Vol.495, pp.135-144
Keywords
NRAS-mutant lung cancerHigh-throughput screeningPan-RAF inhibitorPLK1 inhibitor
Abstract
NRAS mutation is rarely observed in non-small cell lung cancer (NSCLC) patients, and there are no approved treatments for NRAS-mutant NSCLC. Here, we evaluated the effect of pan-RAF inhibitors on human NRAS-mutant NSCLC cell lines and performed high-throughput screening using human kinome small interfering (si) RNA or CRISPR/Cas9 libraries to identify new targets for combination NSCLC treatment. Our results indicate that human NRAS-mutant NSCLC cells are moderately sensitive to pan-RAF inhibitors. High-throughput kinome screenings further showed that G2/M arrest, particularly following knockdown of polo-like kinase 1 (PLK1), can inhibit the growth of human NRAS-mutant NSCLC cells and those treated with the type II pan-RAF inhibitor LXH254. In addition, treatment with volasertib plus LXH254, resulting in dual blockade of PLK1 and pan-RAF, was found to be more effective than LXH254 monotherapy for inhibiting long-term cell viability, suggesting that this combination therapeutic strategy may lead to promising results in the clinic.
ISSN
0304-3835
URI
https://hdl.handle.net/10371/171807
DOI
https://doi.org/10.1016/j.canlet.2020.09.018
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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