Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm, has an escalating incidence and is the second leading cause of cancer-related mortality. Sorafenib and regorafenib remain the only drugs approved for treating advanced HCC. However, the development of invariant resistance to these drugs limits their usefulness. We are exploiting small RNA-interference (siRNA) based technologies to design, modify, synthesize, and test novel second generation chemistry oligonucleotide mimetics to a potent tumour suppressor - microRNA-7 (miR-7) for use as a new therapeutic for HCC. This field has significantly advanced in the past 12 months with the realisation that stable 2nd generation siRNAs conjugated with Gal-NAC (eg Inclisiran) are selectively taken up by hepatocytes (30-70 fold higher) and have potent and sustained (6 month) effects.
Previously we showed miR-7 simultaneously silences expression of multiple oncogenic molecules in multiple signaling pathways that drive other epithelial tumours. Here we show miR-7 mimics significantly inhibit growth of human HCC in vitro and in an in vivo preclinical orthotopic HCC model. The mechanism is in part via direct inhibition of EGFR signaling through the EGFR itself, but also several members of its signaling pathway, especially P-AKT. miR-7 also targets the TYRO3 receptor, a member of the TAM family of receptor tyrosine kinases, whose expression is aberrantly elevated in HCC. TYRO3 can also drive sorafenib resistance in HCC activating the PI3/AKT pathway. However, miR-7 silences TYRO3 expression and inhibits the TYRO3/GAS6 signaling pathway in both sorafenib sensitive and resistant HCC cells. Finally, the interaction between miR-7 and circularRNAs (ciRS-7) in HCC is being explored with our novel miR-7 mimics, as the ciRS-7 sponge may impact on the overall therapeutic potential of miR-7.
Taken together, our data builds the foundation for using a miR-7 mimic as a therapeutic for treating both drug naive and drug resistant HCC.