Dissecting molecular drivers of sorafenib resistance in HCC: integrative genomic analyses of poor and good responders

Introduction Sorafenib was the only approved systemic therapy with demonstrated survival benefit in advanced stage of hepatocellular carcinoma (HCC) for more than a decade. Despite the current success of the multi-tyrosine-kinase inhibitor sorafenib, many of the patients respond poorly to the drug treatment or relapse quickly after initial remission.

Aim The aim of this project was to identify drivers of the sorafenib resistance in the group of HCC patients with the worst response to the treatment.

Methods To identify novel predictive markers of sorafenib response we performed integrative RNA sequencing and whole-exome sequencing analyses. Based on our cohort of 19 HCC patients, we first identified two specific sorafenib-treated subgroups of patients, i.e. long-term responders (n=12) (best) and primary non-responsers (n=7) (worst). 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.

Results Patients with worst response were characterized by significantly shorter treatment duration and poor overall survival than good responders (66,6 months and 133,3 months respectively; p<0,0004). Molecular analyses revealed that 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, NFkB as well as YAP and Hippo signaling were identified to be significantly enriched in this subgroup whereas growth factor signaling as well as KRAS signaling characterized good responders. Importantly, hypoxia of the surrounding tumor microenvironment was significantly enhanced in worst responders. From hypoxia-related targets, we could observe that proteins from the 14-3-3 family (7 isoforms) might play a significant role in acquisition of resistance.

Conclusion Our integrative analyses delineate distinct molecular alterations responsible for response to sorafenib in HCC. Defining the actionable targets of resistance and subsequent inhibition, e.g. components of 14-3-3 protein family, might facilitate to improve the systemic therapy of HCC and is currently under way.

Publication History

Article published online:
04 January 2021