Abstract
Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. Results: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. Conclusion: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio.
Highlights
Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the third leading cause of cancer death and the main cause of death among patients with cirrhosis [1]
Previous works have identified part of the cytotoxicity associated with sorafenib as mitochondrial dependent, with sorafenib activity being potentiated by mitochondrial-directed therapies
In a patient-derived xenograft mouse model, we evaluated the effect sorafenib and regorafenib mouse model, we evaluated the of effect of sorafenib and in hepatocellular carcinoma (HCC)
Summary
Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the third leading cause of cancer death and the main cause of death among patients with cirrhosis [1]. Most liver cancer patients do not benefit from immunotherapy [4] and the efficacy of the multikinase inhibitors (MKIs) sorafenib [5] and lenvatinib [6] in first-line treatment, and regorafenib [7] and cabozantinib [8] in second line, needs to be improved. In HCC, with a complex genetic background and without dependence on specific driver mutations for survival, vulnerabilities created by MKI treatment could provide targets to improve life expectancy [10]. The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment
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