Year-end Sale % OFF 
Abstract
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.
Highlights
Hepatocellular carcinoma (HCC), the most common liver cancer [1], is often diagnosed at an advanced stage with poor prognosis
Taking advantage of this mitochondrial sensitization, BH3-mimetics could interact with anti-apoptotic BCL-2 family members to increase sorafenib efficacy in hepatoma cells
Navitoclax overcame sorafenib resistance in both hepatoma cell lines (Figure 4E, F), while BCL-2 inhibitor ABT-199 did not (Supplementary Figure 5). These results indicate that, changes in BCL-xL have not been observed in hepatocellular carcinoma (HCC) tumors or after sorafenib-exposure, basal BCL-xL levels should be playing an important role in hepatoma cells
Summary
Hepatocellular carcinoma (HCC), the most common liver cancer [1], is often diagnosed at an advanced stage with poor prognosis. Despite several key therapeutic advancements the sole systemic agents with survival benefit are the multikinase inhibitors sorafenib [3] and regorafenib [4]. There is need to develop additional therapeutic agents to further enhance the still limited survival of the patients. The mechanisms for sorafenib and regorafenib escape are not well known. The role of cell death-related pathways involving mitochondria is gaining interest as an alternative approach to target cancers where the dependence on specific driver mutations for survival is not established. In this sense, HCC is a tumor with a complex genetic background where clear druggable addictions have not been validated
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
