Oncogenic β-catenin stimulation of cofilin 1-mediated macropinocytosis is druggable for cancer

<b>Rationale:</b> Although β-catenin is frequently activated in various cancers, no targeted therapies have been approved for clinical use. <b>Methods:</b> High-throughput drug screening was performed to identify potential compounds against β-catenin-activated tumors. The efficacy of identified compounds was assessed in orthotopic β-catenin-driven hepatocellular carcinoma model mice. <b>Results:</b> OSI-027 emerged as the most potent agent that selectively inhibited β-catenin-mutant cells. Mechanistically, β-catenin enhanced the transcription of Cofilin 1 (CFL1), a key stimulator of macropinocytosis, and directly interacted with CFL1 to prevent its inactivation. OSI-027 induced macropinocytosis and subsequently led to methuosis-like cell death of β-catenin-mutant cells. Moreover, both excessive macropinocytosis induced by OSI-027 and macropinocytosis inhibition via CFL1 depletion suppressed β-catenin-driven tumor growth in orthotopic hepatocellular carcinoma model mice. <b>Conclusion:</b> Targeting macropinocytosis represents a promising therapeutic strategy for β-catenin mutant cancers.