NT157 Inhibits Hepatocellular Carcinoma Growth and Sensitizes Cells to Sorafenib
Abstract Background: Sorafenib has been recognized as the standard therapy for advanced hepatocellular carcinoma (HCC). Besides, efficacy of sorafenib was unsatisfactory and vast patients are resistant to sorafenib. Thus, molecular mechanisms underlying regulation of sorafenib resistance and seeking potential strategy to improve its efficacy have attracted much attention. As a small-molecule inhibitor of IGF-1R, NT157 has potent antitumor activity against some human cancers. However, whether NT157 has potential anti-tumor effects and its molecular mechanisms in HCC remain poorly understood. Methods: We assessed the effects and explored the mechanism of NT157 and sorafenib as single agents or in combination with sorafenib in HCC cells and mouse model. Further, we further demonstrated that NT157 reversed resistance to sorafenib in HCC.Results: Here, we found NT157 inhibited HCC growth and induced apoptosis in vitro and in vivo. In terms of mechanism, NT157 phosphorylated IRS-1 through ERK-MAPK signaling to be degraded by the ubiquitin-proteasome pathway, lowered p-AKT to deactivate IGF-1R signaling to inhibit proliferation and induce apoptosis. Surprisingly, we further demonstrated that NT157 acted synergistically with sorafenib to inhibit proliferation and contributed to sensitize HCC cells to sorafenib by down-regulation of p-AKT. Conclusions: Overall, our findings provide a translational rationale for inhibition of IGF-1R and downstream signaling pathways by NT157 as a novel targeted therapy alone or combined with sorafenib in HCC.