Sorafenib and SIAIS361034, a novel PROTAC degrader of BCL-x_L, display synergistic antitumor effects on hepatocellular carcinoma with minimal hepatotoxicity

The overexpression of BCL-x_L is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-x_L and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-x_L through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-x_L in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-x_L and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-x_L and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-x_L and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-x_L and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma.