Intra- and inter-patient diversity in hepatocellular carcinoma based on phosphorylation profiles-A pilot study in a single institution.

Abstract

Background: Recent studies have addressed the efficacy of targeted drugs against hepatocellular carcinoma. However, most tumors escape a single kinase inhibition; co-inhibition of additional signaling pathways re-sensitizes resistant cancer cells to targeted drugs, thus reinforcing the importance of combination therapy for drug-resistant tumors. This study aimed to clarify the phosphorylation profiles of representative cancer-related tyrosine kinases in hepatocellular carcinoma to focus on potential therapeutic targets and to investigate the possibility of expanding combination therapy options using targeted drugs.

Materials and methods: Patients' whole blood, hepatocellular carcinoma tissue, and adjacent hepatic tissues were obtained during surgeries from 10 patients. All patients showed negative results for hepatitis B and hepatitis C RNA and none had a history of heavy drinking. The activation of receptor tyrosine kinases (RTKs) was analyzed by using a human RTK phosphorylation antibody array.

Results: Among 62 different phospho-RTKs, 26 were activated in tumor tissues, of which ACK1, Dtk, Fyn, and Lyn were positive in 9 out of 10 cases. The median concordance rates of activated tumor and serum RTKs in each patient was 50%. There was an inter- and intra-patient diversity of phosphorylation profiles in the serum, tumor of resected specimens, and non-tumor tissue of resected specimens in the same patients.

Conclusion: There was an intra- and inter- patient diversity in the activation of important and representative cancer-related RTKs. Expanding on this approach will allow us to learn how to predict the best combination of targets for each patient and to prioritize those combinations for clinical testing.