Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27193833.
- Also identified by DOI 10.1038/ncomms11363 and PMC identifier 4873974.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21(WAF1/CIP1), leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21(WAF1/CIP1), either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21(WAF1/CIP1). Co-administration of BI-2536 and fasudil either in the LSL-KRAS(G12D) mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers.
Medical subject headings
- Antineoplastic Agents
- Cell Cycle Proteins
- Enzyme Inhibitors
- Lung Neoplasms
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins p21(ras)
- rho-Associated Kinases