Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and the fourth leading cause of cancer-related deaths worldwide. The multikinase inhibitor sorafenib is the only approved drug to treat HCC and on average enhances survival by three months. Thus, the efficacy of current HCC treatment options is very limited. Studies in the context of our ERC-Synergy grant revealed that sorafenib resistance correlates with upregulation of mammalian target of rapamycin complex 1 (mTORC1) signaling. The central role of mTORC1 in conferring therapy resistance suggests that effective therapy against HCC may require combination of a primary inhibitor (e.g., sorafenib) and an mTORC1 inhibitor. The mTORC1 inhibitor rapamycin and its derivatives (rapalogs) are approved for a few advanced cancers, but not for HCC. Their clinical applicability is limited by their effectiveness and safety. Rapalogs fail to completely inhibit mTORC1 as they have little effect on inhibiting phosphorylation of 4E-BP, one of the two main targets of mTORC1. Moreover, rapamycin and rapalogs also inhibit mTORC2 when chronically administered, leading to undesirable effects such as hyperglycemia, hyperlipidemia, and insulin resistance. We have established a biophysical assay to identify selective mTORC1 inhibitors with a novel, rapalogunrelated, mechanism of action. We predict these inhibitors to be more selective, more effective, and potentially safer than mTORC1 inhibitors currently used in the clinic. In this Proof of Concept project, we aim to study the pharmacological potential of selective and efficient mTORC1 inhibition alone or in combination therapy with sorafenib to treat HCC.