Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma.

Simple Summary: In the past decade, tyrosine kinase inhibitors sorafenib and regorafenib have been standard treatments for advanced liver cancer. Previous studies have associated sorafenib with inflammasome activation, but its therapeutic role in patients has not been explored. Our study found that both treatments altered inflammasome-related gene expression, showing a similar transcriptomic pattern in a mouse model of liver cancer. In accordance with public databases, inflammasome genes are associated with a poorer prognosis in male liver cancer patients, without changes in females. Thus, we analyzed biopsies from hepatocellular carcinoma patients treated with sorafenib/regorafenib and confirmed inflammasome activation. In experimental models, inflammasome inhibition enhanced sorafenib effectiveness, demonstrating its potential to overcome therapy resistance and improve its efficacy for liver cancer treatment. During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC. [ABSTRACT FROM AUTHOR]

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