Integrative genomic analyses identified 14-3-3 zeta as a potential molecular driver of sorafenib resistance in HCC patients

Introduction Multi-tyrosine-kinase inhibitor sorafenib demonstrated a survival benefit in advanced stage of hepatocellular carcinoma (HCC), but many of the patients respond poorly to the drug treatment.

Aim Dissecting molecular drivers of sorafenib resistance in HCC was of major importance in this project, focusing on the group of HCC patients with the worst response to the treatment.

Methods Integrative RNA sequencing and whole-exome sequencing analyses were used to identify predictive markers of sorafenib resistance based on our cohort of 19 HCC patients. Potential drivers of drug resistance were evaluated by Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Validation was performed in our in vitro model of sorafenib resistance by western blot and in publicly available data sets, followed by siRNA inhibition.

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 poor responder group was associated with activation of pathways commonly linked to proliferation, oxidative stress, and inflammation. Furthermore, genes sets associated with activation of Pi3K/AKT/mTOR, MAPK1, NF-kB as well as YAP and Hippo signaling were identified to be significantly enriched in this subgroup. Importantly, hypoxia of the surrounding tumor microenvironment was significantly enhanced in the worst responders. From hypoxia-related targets, we could observe that 14-3-3 zeta protein (member of the 14-3-3 protein family) might play a significant role in the acquisition of resistance.

Conclusion Defining the actionable targets of resistance and subsequent inhibition, e.g. 14-3-3 zeta protein might be of great help to delineate distinct molecular alterations driving sorafenib resistance. Our results should improve the systemic therapy of HCC and it is currently underway.

Publication History

Article published online:
07 September 2021