Messner 2020 Thesis

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Messner M (2020) Sorafenib resistance of hepatocellular carcinoma. PhD Thesis 130.


Messner Martina (2020) PhD Thesis

Abstract: Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). Nonetheless, its use is hampered by the frequent occurrence of drug resistance and up to 80% of patients treated with sorafenib suffer from side effects necessitating dose reduction, β€œdrug holidays” or treatment termination. This study aimed to extend the current knowledge on the mechanism of sorafenib resistance with focus on a potential relapse of tumor growth after sorafenib withdrawal. Tumor growth resumption essentially contributes to a poor therapy outcome of sorafenib, but to date there is no therapeutic strategy to address this problem.

Herein, a robust sorafenib resistance HCC cell model was established and characterized by mass spectrometry (MS)-based proteomics and lipidomics, in order to reveal targets for a potential second-line therapy after sorafenib failure. The impact of continuous sorafenib exposure and drug withdrawal on cellular metabolism and mitochondrial functionality was then specified by glycolytic stress tests, high resolution respirometry and transmission electron microscopy (TEM).

We found that acquired chemoresistance of HCC is accompanied by severe mitochondrial damage and impairment of the electron transport chain (ETC). These sorafenib-resistant cells, fail to maintain their cellular redox homeostasis and obtain broad chemotherapeutic cross-resistance. In fact, sorafenib withdrawal leads to a rapid resumption of tumor cell proliferation, while cells resensitize towards chemotherapeutic treatment. Upon this tumor β€œrebound” growth, regeneration of the mitochondrial integrity and a boost of oxidative phosphorylation were observed. Inhibition of mitochondrial biogenesis by bacterial translation-inhibiting antibiotics, such as tigecycline (TGC), decreases the renewal of critical ETC subunits and limits the regeneration of reducing equivalents. Thereby, TGC efficiently blocks the oxidative glutamine metabolism of the tricarboxylic acid (TCA) cycle, which fuels rapid tumor regrowth. Importantly, TGC prevents the therapy-limiting tumor relapse after sorafenib withdrawal in vitro and in ectopic murine HCC xenografts in vivo.

Approved bacterial translation inhibiting antibiotics are generally characterized by favorable safety profiles with low incidence of adverse side-effects and good experience on dosing schedules, therefore holding tremendous promise for clinical translation. With regard to the clinical potential of the approved antibiotic TGC, we present a novel promising second-line therapeutic approach for HCC patients with progressive disease during sorafenib therapy, but also for patients who need a treatment interruption due to severe adverse events. Our study encourages a clinical evaluation of TGC for a new designation in advanced-stage HCC, to prevent the tumor growth resumption after therapy termination and prolong the patient’s life expectancy after sorafenib failure.

β€’ Bioblast editor: Plangger M

Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology  Pathology: Cancer 

Organism: Human  Tissue;cell: Liver  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 


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