Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors.

Abstract

BACKGROUND:

Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.

METHODS:

We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin-like growth factor-binding protein-1 (IGFBP-1) levels of 31 lenvatinib-treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain- and loss-of-function experiments were performed.

RESULTS:

In the patient cohort, IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling. IGFBP-1 stimulated angiogenesis through activation of the integrin α5β1-focal adhesion kinase pathway. Consequently, loss of IGFBP-1 and integrin α5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.

CONCLUSIONS:

Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP-1, which promoted angiogenesis through activating the IGFBP-1-integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

• Authors: Hiroyuki Suzuki, Hideki Iwamoto, Takahiro Seki, Toru Nakamura, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Yasuko Imamura, Takashi Niizeki, Masahito Nakano, Shigeo Shimose, Tomotake Shirono, Yu Noda, Naoki Kamachi, Miwa Sakai, Kazutoyo Morita, Masamichi Nakayama, Tomoharu Yoshizumi, Ryoko Kuromatsu, Hirohisa Yano, Yihai Cao, Hironori Koga, Takuji Torimura
• Journal: Cancer communications (London, England) (Cancer Commun (Lond)) Vol. 43 Issue 4 Pg. 415-434 (04 2023) ISSN: 2523-3548 [Electronic] United States
• PMID: 36825684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

Chemical References

• lenvatinib
• Tyrosine Protein Kinase Inhibitors
• Insulin-Like Growth Factor Binding Protein 1
• Integrin alpha5beta1
• Somatomedins

Topics

• Humans
• Animals
• Mice
• Carcinoma, Hepatocellular (pathology)
• Liver Neoplasms (pathology)
• Tyrosine Protein Kinase Inhibitors
• Insulin-Like Growth Factor Binding Protein 1 (pharmacology)
• Integrin alpha5beta1 (metabolism)
• Proteomics
• Retrospective Studies
• Somatomedins (metabolism)
• Hypoxia