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

Author:

Suzuki Hiroyuki12ORCID,Iwamoto Hideki123,Seki Takahiro4,Nakamura Toru12,Masuda Atsutaka12,Sakaue Takahiko12,Tanaka Toshimitsu12,Imamura Yasuko2,Niizeki Takashi1,Nakano Masahito1,Shimose Shigeo1,Shirono Tomotake1,Noda Yu1,Kamachi Naoki1,Sakai Miwa1,Morita Kazutoyo5,Nakayama Masamichi6,Yoshizumi Tomoharu5,Kuromatsu Ryoko12,Yano Hirohisa6,Cao Yihai4ORCID,Koga Hironori12,Torimura Takuji12

Affiliation:

1. Division of Gastroenterology Department of Medicine Kurume University School of Medicine Kurume City Fukuoka Japan

2. Liver Cancer Research Division Research Center for Innovative Cancer Therapy Kurume University Kurume City Fukuoka Japan

3. Iwamoto Internal Medicine Clinic Kitakyushu City Fukuoka Japan

4. Department of Microbiology Tumor and Cell biology Karolinska Institutet Stockholm Sweden

5. Department of Surgery and Science Graduate School of Medical Science Kyushu University Fukuoka City Fukuoka Japan

6. Department of Pathology Kurume University School of Medicine Kurume City Fukuoka Japan

Abstract

AbstractBackgroundAntiangiogenic 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.MethodsWe 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.ResultsIn 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.ConclusionsTogether, 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.

Funder

Takeda Science Foundation

Publisher

Wiley

Subject

Cancer Research,Oncology

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