Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach

By Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

Sorafenib, a multikinase inhibitor, is a first-line treatment for advanced hepatocellular carcinoma, but its longterm effectiveness is limited by the emergence of resistance mechanisms. HSP90 plays a critical role in conferring resistance to sorafenib in HepG2 cells under hypoxic
conditions and N-Nitrosodiethylamine-exposed mice. To augment the effects of sorafenib, we investigated the use of ganetespib, an HSP90 inhibitor. We observed a significant negative correlation between LAMP2 and MLKL. Combining ganetespib with sorafenib showed a synergistic cytotoxic effect and resulted in the accumulation of p62 and inhibition of macroautophagy. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

Effect of SFB and GTSB on % growth inhibition (A)
and combination index (B). The CTC50 values represent the
concentration at which 50% of cell growth is inhibited and
providing insights into the drugs’ potency against the
tested cells. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Effect of SFB and the combination of GTSB and SFB on the levels of HSP90 (A), HSP70 (B), LAMP2 (C), MLKL (D), and p62 (E) in HepG2 cells. Additionally, a
correlation analysis of the measured parameters was conducted (F). Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Effect of SFB and the combination of GTSB and SFB on the number of
nodules per liver (A), liver index (B), AFP (C), and ROS (D). Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Liver specimens were stained with H&E to evaluate the effect of different treatments on hepatic architecture and the development of hepatocellular carcinoma. These findings suggest that SFB and the combination of SFB with GTSB may have therapeutic potential for treating HCC. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.
Correlation analysis for the effect of SFB and the combination of GTSB and SFB on the measured parameters (HSP90, HSP70, LAMP2, MLKL, p62, HIF-1α,
and VEGF).Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

The proper transportation of proteins across the lysosomal membrane
in the CMA process is dependent on essential components,
including HSP90 and LAMP2. Our study indicates that under hypoxic
conditions, there is a significant upregulation of HSP90 and LAMP2
expression. Our findings suggest that MLKL, which is the mediator of
necroptosis, can be degraded through the CMA pathway under hypoxia.
Furthermore, our preclinical data show that HSP90 plays a critical role
in conferring resistance to SFB under hypoxia by inhibiting necroptosis.
Combining GTSB with SFB may offer a promising therapy for HCC. Copyright Sameh Saber, Alexandru Hasan, Simona Cavalu et al.

Full text available at: https://doi.org/10.1016/j.biopha.2023.114918