Journal
ONCOGENE
Volume 36, Issue 10, Pages 1339-1350Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.308
Keywords
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Funding
- NIH/NCI ICBP [U54-CA112970]
- CCBTP training grant from the CPRIT
- NIH [UH2 TR000943]
- RGK Foundation
- CPRIT [RP110595]
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KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3' UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3' UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivo and in vivo studies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.
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