14-3-3 scaffold protein family as a potential molecular driver of sorafenib resistance in HCC patients

 

Introduction The hallmarks of many cancers, including hepatocellular carcinoma (HCC), are apoptosis resistance, poor response to the drug treatment or quick relapse after initial remission.

Aim To dissect molecular drivers of drug resistance frequently observed in HCC, particularly in the patients who demonstrated the worst response to sorafenib.

Methods Integrative RNA sequencing and whole-exome sequencing analyses were employed to identify predictive markers of sorafenib resistance based on our cohort of 19 HCC patients. Potential drivers of drug resistance were evaluated by IPA and GSEA. Validation was performed in our in vitro model of sorafenib resistance by western blot and in publicly available data sets (GEPIA), followed by siRNA or peptide (R18) inhibition of selected molecular target candidates.

Results Patients with worst response (n=7) were characterized by significantly shorter treatment duration and poor overall survival than good responders (n=12) (66,6 months and 133,3 months, respectively; p < 0,0004). Molecular analyses revealed that the worst subgroup was associated with activation of ERK and hypoxia-related scaffold proteins from the 14-3-3 protein family. Further, in our focus group, analysis based on gene expression signature showed significant enrichment of gene sets associated with Hippo/YAP signaling, ERK signaling and hypoxia. From hypoxia-related targets, we could observe that 14-3-3 zeta and sigma proteins might play a significant role in the acquisition of drug resistance.

Conclusion Defining the actionable targets of resistance and subsequent inhibition, e. g. 14-3-3 zeta and/or sigma protein might be of great help to delineate distinct molecular alterations driving sorafenib resistance.

Publication History

Article published online:
26 January 2022

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