Author Identifier (ORCID)

Andrew J. Woo: https://orcid.org/0000-0003-1198-6373

Abstract

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 overcame pan-TKI resistance. In HCC patient datasets, elevated CAV1 mRNA was observed in sorafenib non-responders, and single cell RNA-sequencing of HCC patient tumours revealed a rare population of CAV1+ cancer cells associated with recurrence. High CAV1 expression was specific to HBV+ HCC patients and independently predicted poor survival. Further, targeting of CAV1, AXL or FGFR4 effectively overcame TKI resistance in HCC patient derived organoids (PDOs). Our findings highlight a previously unrecognized role for CAV1-driven signalling in sustaining tumour dormancy, a critical and challenging therapeutic barrier underlying recurrence and pan-TKI resistance in HCC. Therapeutically targeting these pathways offer a promising and novel strategy to eliminate dormant tumour cells, thereby overcoming resistance and improving treatment outcomes.

Document Type

Journal Article

Date of Publication

7-25-2025

Volume

16

Issue

1

PubMed ID

40715090

Publication Title

Cell Death Disease

Publisher

Nature

School

Centre for Precision Health

RAS ID

82684

Funders

The Cancer Council Western Australia / National Health and Medical Research Council / Cancer Council NSW / McCusker Foundation Fellowship / The Liver Cancer Collaborative / The MACA ECR Award 2022 / The Heart Foundation Future Leader Fellowship

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Comments

Kabir, T. D., Beck, S., Stuart, L. M., Li, J., Hou, R., Liu, P., Margolius, S., Kim, C., Choi, Y. S., Bastow, E. R., Beveridge, D. J., Spalding, L., Li, Z., Ginhoux, F., Chow, P., Phillips, M., Redfern, A. D., Yeoh, G. C., Forrest, A., . . . Leedman, P. J. (2025). Inhibition of the caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma. Cell Death and Disease, 16. https://doi.org/10.1038/s41419-025-07887-4

First Page

561

Included in

Oncology Commons

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Link to publisher version (DOI)

10.1038/s41419-025-07887-4