Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma
- Resource Type
- Authors
- Pinato, DJ; Brown, MW; Trousil, S; Aboagye, EO; Beaumont, J; Zhang, H; Coley, HM; Mauri, FA; Sharma, R
- Source
- British Journal of Cancer
- Subject
- Adult
Male
EXPRESSION
MECHANISM
Carcinoma, Hepatocellular
Epithelial-Mesenchymal Transition
Hepatocellular carcinoma
Antineoplastic Agents
Article
ACTIVATION
TUMOR PHENOTYPE
Cell Movement
Target identification
Cell Line, Tumor
Proto-Oncogene Proteins
Humans
HETEROGENEITY
1112 Oncology and Carcinogenesis
RNA, Messenger
Oncology & Carcinogenesis
neoplasms
Aged
Science & Technology
Liver Neoplasms
SYSTEMIC THERAPIES
Receptor Protein-Tyrosine Kinases
INHIBITOR
Middle Aged
Sorafenib
Axl Receptor Tyrosine Kinase
CANCER
digestive system diseases
Oncology
PERSPECTIVES
Drug Resistance, Neoplasm
SURVIVAL
Female
Life Sciences & Biomedicine
- Language
- English
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.