Effects of sorafenib dose on acquired reversible resistance and toxicity in hepatocellular carcinoma
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes associés à l'apparition d'une résistance au sorafénib dans le traitement d'un carcinome hépatocellulaire
Acquired evasive resistance is a major limitation of hepatocellular carcinoma (HCC) treatment with the tyrosine kinase inhibitor (TKI) sorafenib. Recent findings suggest that resistance to sorafenib may have a reversible phenotype. Additionally, loss of responsiveness has been proposed to be due to a gradual decrease in sorafenib plasma levels in patients. Here, the possible mechanisms underlying reversible sorafenib resistance were investigated using a Hep3B-hCG orthotopic human xenograft model of locally advanced HCC. Tissue and plasma sorafenib and metabolite levels, downstream anti-tumor targets and toxicity were assessed during standard and dose-escalated sorafenib treatment. Drug levels were found to decline significantly over time in mice treated with 30 mg/kg sorafenib coinciding with the onset of resistance but a greater magnitude of change was observed in tissues compared to plasma. Skin rash also correlated with drug levels and tended to decrease in severity over time. Drug level changes appeared to be partially tumor-dependent involving induction of tumoral CYP3A4 metabolism, with host pre-treatment alone unable to generate resistance. Escalation from 30 to 60 mg/kg sorafenib improved anti-tumor efficacy but worsened survival due to excessive body weight loss. Microvessel density was inhibited by sorafenib treatment but remained stable over time and dose increase. In conclusion tumor CYP3A4 induction by sorafenib is a novel mechanism to account for variability in systemic drug levels, however declining systemic sorafenib levels may only be a minor resistance mechanism. Escalating the dose may be an effective treatment strategy, provided toxicity can be controlled.
Cancer Research 2015