Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p

Abstract

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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Acknowledgements

All the data reported in the paper are presented. The microarray data are available from GEO under the accession number GSE73194. The work presented here was funded by NIH/NCI ICBP grant U54-CA112970 (Project 2 PI-JWG, Project 4 Co-PI’s PTR and GBM), VS was funded by the CCBTP training grant from the CPRIT, and grants from the NIH (UH2 TR000943), the RGK Foundation, and CPRIT RP110595 (AKS).

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Correspondence to P T Ram.

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Seviour, E., Sehgal, V., Mishra, D. et al. Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p. Oncogene 36, 1339–1350 (2017). https://doi.org/10.1038/onc.2016.308

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