Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma.

Abstract

BACKGROUND:

Aberrant activation of Axl is implicated in the progression of hepatocellular carcinoma (HCC). We explored the biologic significance and preclinical efficacy of Axl inhibition as a therapeutic strategy in sorafenib-naive and resistant HCC.

METHODS:

We evaluated Axl expression in sorafenib-naive and resistant (SR) clones of epithelial (HuH7) and mesenchymal origin (SKHep-1) using antibody arrays and confirmed tissue expression. We tested the effect of Axl inhibition with RNA-interference and pharmacologically with R428 on a number of phenotypic assays.

RESULTS:

Axl mRNA overexpression in cell lines (n = 28) and RNA-seq tissue datasets (n = 373) correlated with epithelial-to-mesenchymal transition (EMT). Axl was overexpressed in HCC compared to cirrhosis and normal liver. We confirmed sorafenib resistance to be associated with EMT and enhanced motility in both HuH7-SR and SKHep-1-SR cells documenting a 4-fold increase in Axl phosphorylation as an adaptive feature of chronic sorafenib treatment in SKHep-1-SR cells. Axl inhibition reduced motility and enhanced sensitivity to sorafenib in SKHep-1SR cells. In patients treated with sorafenib (n = 40), circulating Axl levels correlated with shorter survival.

CONCLUSIONS:

Suppression of Axl-dependent signalling influences the transformed phenotype in HCC cells and contributes to adaptive resistance to sorafenib, providing a pre-clinical rationale for the development of Axl inhibitors as a measure to overcome sorafenib resistance.

• Authors: David J Pinato, Matthew W Brown, Sebastian Trousil, Eric O Aboagye, Jamie Beaumont, Hua Zhang, Helen M Coley, Francesco A Mauri, Rohini Sharma
• Journal: British journal of cancer (Br J Cancer) Vol. 120 Issue 5 Pg. 512-521 (03 2019) ISSN: 1532-1827 [Electronic] England
• PMID: 30765873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Proto-Oncogene Proteins
• RNA, Messenger
• Sorafenib
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase
• AXL protein, human

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy)
• Cell Line, Tumor
• Cell Movement
• Drug Resistance, Neoplasm (genetics)
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Liver Neoplasms (drug therapy)
• Male
• Middle Aged
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics)
• RNA, Messenger (metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Sorafenib (pharmacology, therapeutic use)
• Axl Receptor Tyrosine Kinase