article · Biomedicine & Pharmacotherapy
Sorafenib is a standard treatment for advanced liver cancer, but prolonged use often triggers resistance due to reduced oxygen levels inside tumours. This study investigates whether ganetespib, an inhibitor of the heat shock protein HSP90, can overcome this resistance. In cell cultures and mouse models of hepatocellular carcinoma, HSP90 was found to protect tumours under low-oxygen conditions by stabilising HIF-1alpha and blocking a form of cell death known as necroptosis. Adding ganetespib reversed these effects by activating necroptosis and destabilising HIF-1alpha, whilst also suppressing macroautophagy. In animal trials, pairing ganetespib with sorafenib produced synergistic cytotoxic effects, significantly reduced liver surface nodules, lowered liver index values, and decreased alpha-fetoprotein levels. These preclinical findings indicate that combining ganetespib with sorafenib can counteract drug resistance and enhance therapeutic outcomes in liver cancer.
Advanced liver cancer is difficult to manage because tumours frequently develop resistance to standard therapies like sorafenib. Identifying that an HSP90 inhibitor can restore tumour sensitivity and trigger alternative cell death pathways gives oncologists and biomedical researchers a clearer biological roadmap to counter treatment failure in patients with advanced hepatocellular carcinoma.
The work highlights a combination therapeutic strategy that could interest biopharmaceutical developers focused on oncology drug pipelines. The prospective application is a combination therapy for sorafenib-resistant liver cancer. However, because the evidence is strictly derived from laboratory cell lines and mouse models, the concept remains at an early preclinical stage, requiring substantial translational validation and clinical trials before any commercial or clinical adoption.
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Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its long-term effectiveness is limited by the emergence of resistance mechanisms. One such mechanism is the reduction of microvessel density and intratumoral hypoxia caused by prolonged sorafenib treatment. Our research has demonstrated that HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic conditions and N-Nitrosodiethylamine-exposed mice as well. This occurs through the inhibition of necroptosis on the one hand and the stabilization of HIF-1α on the other hand. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We found that ganetespib activated necroptosis and destabilized HIF-1α under hypoxia, thus enhancing the effectiveness of sorafenib. Additionally, we discovered that LAMP2 aids in the degradation of MLKL, which is the mediator of necroptosis, through the chaperone-mediated autophagy pathway. Interestingly, we observed a significant negative correlation between LAMP2 and MLKL. These effects resulted in a reduction in the number of surface nodules and liver index, indicating a regression in tumor production rates in mice with HCC. Furthermore, AFP levels decreased. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. These findings suggest that the combined therapy of ganetespib and sorafenib may offer a promising approach for the treatment of hepatocellular carcinoma by activating necroptosis, inhibiting macroautophagy, and exhibiting a potential antiangiogenic effect. Overall, continued research is critical to establish the full therapeutic potential of this combination therapy.
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DOI: 10.1016/j.biopha.2023.114918
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