Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma

Liver cancer is the fourth most common cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co-inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well-tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.

Automated summary

Liver cancer is a major cause of cancer-related death globally, with limited therapeutic options available. Reactivation of receptor tyrosine kinases (RTK) has been identified as a mechanism of resistance to targeted therapies in various cancers. In this study, we demonstrate that multiple RTK are activated upon mTOR inhibition in hepatocellular carcinoma (HCC), leading to reactivation of the mTOR pathway. Co-inhibition of mTOR and SHP2, a downstream target of RTK, synergistically induces apoptosis and effectively impairs tumor growth in HCC mouse models. These findings suggest a novel rational combination therapy for HCC.