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 p21WAF1/CIP1, leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21WAF1/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 p21WAF1/CIP1. Co-administration of BI-2536 and fasudil either in the LSL-KRASG12D 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.
Highlights
No effective targeted therapies exist for cancers with somatic KRAS mutations
Several genome-wide RNA interference (RNAi) screens and other technologies have identified a list of candidate genes, including TANK-binding kinase 1 (TBK1)[14], serinethreonine kinase STK33 and heat-shock protein 90 (HSP90; the inhibition of HSP90 involves the degradation of STK33)[16], polo-like kinase 1 (PLK1)[17,18], cyclin-dependent kinase 4 (CDK4)[19], transcription factor (TF) GATA2, evolutionarily conserved gene enhancer of rudimentary homologue (ERH)[18], transforming growth factor b-activated kinase 1 (TAK1)[22], anti-apoptotic BH3 family member BCL-XL23, mitotic regulators[17,21], proteasome and topoisomerase components[17,20,21] and genes that are involved in glucose metabolism[24]
We evaluated the impact of the KRAS-mutant genotype on a panel of agents that directly or indirectly targeted RAS effector pathways and had a potential for synthetic lethal interaction with mutant KRAS (Supplementary Table 1)
Summary
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. Due to this issue, direct pharmacologic targeting of activated RAS protein with small molecules seems to be an impossible task, small molecules that bind to allosteric regulatory sites on KRAS (G12C) have shown preclinical benefits[9] To overcome this limitation, investigators have explored other potential therapeutic approaches, such as indirectly targeting mutant KRAS, developing drugs to inhibit downstream KRAS effectors or using unbiased searches for targets that are synthetically lethal with mutant KRAS3,10. To advance the discovery of drugs against mutant KRAS tumours, synthetic lethal chemical screens have emerged and represent a direct and complementary approach to identifying drugs that target the essential signalling networks for the growth of KRASmutant tumours Such an approach could provide immediately usable translational therapeutic strategies by identifying drugs that are already available in clinic. The combined inhibition of KRAS downstream effectors has shown toxicity and disappointing efficacy in clinical testing[27], searching for novel and clinically applicable anti-RAS drug pairs is of great importance
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