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.

Efficacy of Lenvatinib Combined with Transcatheter Intra-Arterial Therapies for Patients with Advanced-Stage of Hepatocellular Carcinoma: A Propensity Score Matching

“…Guo et al also demonstrated that YRDC, which was capable of binding transfer RNA (tRNA), was related to acquired resistance to LEN through regulation of the protein translation of KRAS through the modification of tRNA [ 26 ]. We also previously reported the acquired resistance mechanism of LEN due to the insulin-like growth factor-binding protein-1 (IGFBP-1) protein [ 27 ]. IGFBP1 is promoted by LEN-induced ischemia, and it could induce neo-angiogenesis in a VEGF-independent manner.…”

Lenvatinib in hepatocellular carcinoma: Resistance mechanisms and strategies for improved efficacy

“…Eukaryotic cells can prevent hypoxia by activating the HIF pathway and modifying the TME to adapt to hypoxic conditions. Furthermore, hypoxia is closely associated with tumour proliferation and acquired resistance to various therapies 99,100 …”

“…In addition, they found that the combination of the FACT complex inhibitor curaxin and VEGF antibody drugs (e.g., lenvatinib, bevacizumab) showes an excellent synergistic effect and enhances the anticancer effect of antiangiogenic therapy. Furthermore, the combination of lenvatinib with IGFBP‐1 neutralizing antibodies or integrin α5β1 inhibitors could inhibit hypoxia‐induced IGFBP‐1 and downstream integrin α5β1/FAK/ERK signalling, resulting in significantly improved drug resistance 100 . For abnormal metabolic alterations, including increased glucose metabolism and increased cholesterol synthesis in CSCs, appropriate inhibitor combinations can substantially inhibit tumour growth by restoring lenvatinib sensitivity in HCC; these inhibitors include PFKFB3 silencers, PFKFB3 suppressors (i.e., PFK15), and the cholesterol‐lowering drug simvastatin 114,116 …”

“…Furthermore, hypoxia is closely associated with tumour proliferation and acquired resistance to various therapies. 99,100 Under hypoxic conditions, HIF-1α and HIF-2α exhibit robust expression in HCC; these expression patterns contribute to increased production of angiogenic factors, such as vascular endothelial growth factor (VEGF), to drive angiogenesis. 101 Hypoxia-inducible factor 1 (HIF-1), a transcription factor that rapidly activates a range of gene transcription, can ensure the survival of cancer cells in hypoxia and further imbue cancer cells with aggressive properties (self-renewal, metastasis, angiogenesis and treatment resistance).…”

“…106 Suzuki et al revealed that hypoxia-induced serum insulin-like growth factor binding protein 1 (IGFBP-1), is significantly correlated with the therapeutic effect of lenvatinib by regulating the levels of HIF-1α and HIF-2α and promoting angiogenesis. 100 Thus, the authors suggested that elevated serum IGFBP-1 could serve as a biomarker for prognostic monitoring in patients with advanced HCC during receipt of lenvatinib or other TKIs.…”