Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma

作者：Tasnuva D. Kabir, Samuel J. Beck, Lisa M. Stuart, Ji Li, Rui Hou, Peiwen Liu, Shelby Margolius, Claire Kim, Yu Suk Choi, Edward Bastow, Dianne J. Beveridge, Lisa Spalding, Ziyi Li, Florent Ginhoux, Pierce K. H. Chow, Michael Phillips, Andrew Redfern, on behalf of The Liver Cancer Collaborative, Janina E. E. Tirnitz-Parker, Michael C. Wallace, Louise N. Winteringham, Benjamin J. Dwyer, Gayatri Shirolkar, Sara Pasic, Larissa Dymond, Jonathan Tibballs, George C. Yeoh, Alistair Forrest, Andrew J. Woo, Ankur Sharma, Jacob George, Geoffrey McCaughan, Peter J. Leedman · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07887-4 · 被引用次数：13 · 研究领域：Caveolin-1 and cellular processes、Phagocytosis and Immune Regulation、Pancreatic and Hepatic Oncology Research

Resistance to multi-tyrosine kinase inhibitors (TKI) is a major clinical concern in advanced hepatocellular carcinoma (HCC). Herein, we aimed to uncover the mechanisms underlying pan-TKI resistance and to identify potential therapeutic targets. We used multiple TKI-resistant HCC cell lines to identify caveolin-1 (CAV1) as a key driver of therapeutic resistance. CAV1 downregulation induced apoptosis, inhibited metastasis and restored TKI sensitivity in both inherent and acquired TKI-resistant HCC cells. Mechanistically, in acquired TKI-resistant cells aberrant CAV1/STAT3/P70S6K signalling is required for their survival, motility, and invasiveness. CAV1 inhibition reduced expression of dormancy regulators E-cadherin, RAC1 and p21, enhanced cancer stemness markers, and disrupted downstream STAT3/P70S6K and AMPKα signalling pathways, prompting cancer cells to exit from dormancy and initiate autophagy-induced cell death. Furthermore, selective inhibition of AXL and FGFR4 downstream of the CAV1 pathway sensitized TKI-resistant cells to sorafenib and lenvatinib, respectively. In addition, microRNA-7-5p (miR-7) was identified as an endogenous regulator of CAV1; and miR-7's inhibitory effect on CAV1 and FGFR4 suppressed the STAT3/P70S6K pathway, promoted autophagy and triggered apoptosis in lenvatinib-resistant cells. Combination therapy using either lenvatinib or sorafenib and selective CAV1 inhibitors (e.g., siCAV1/miR-7), or AXL/FGFR4 inhibitors (e.g., BGB324/BLU9931) effectively o...