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Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK.


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.

SUBMITTER: Wang J 

PROVIDER: S-EPMC4873974 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK.

Wang Jieqiong J   Hu Kewen K   Guo Jiawei J   Cheng Feixiong F   Lv Jing J   Jiang Wenhao W   Lu Weiqiang W   Liu Jinsong J   Pang Xiufeng X   Liu Mingyao M  

Nature communications 20160519


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  ...[more]

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