Combined blockade of polo-like kinase and pan-RAF is effective against NRAS-mutant non-small cell lung cancer cells.
Cancer Lett
; 495: 135-144, 2020 12 28.
Article
in En
| MEDLINE
| ID: mdl-32979462
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pteridines
/
Carcinoma, Non-Small-Cell Lung
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Protein Kinase Inhibitors
/
GTP Phosphohydrolases
/
Lung Neoplasms
/
Membrane Proteins
/
Mutation
Limits:
Aged
/
Humans
/
Male
Language:
En
Journal:
Cancer Lett
Year:
2020
Document type:
Article