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Autophagy and biotransformation affect sorafenib resistance in hepatocellular carcinoma

ABSTRACT: As a first-line drug for treating advanced hepatocellular carcinoma, the resistance to sorafenib has always attracted attention. However, most attention has been focused on a series of mechanisms related to drug resistance caused after sorafenib treatment. In this study, we used proteomic techniques to explore the potential mechanisms by which pre-treatment factors affect sorafenib resistance.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wantao Ying

PROVIDER: PXD040371 | iProX | Fri Feb 24 00:00:00 GMT 2023

REPOSITORIES: iProX

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Autophagy and biotransformation affect sorafenib resistance in hepatocellular carcinoma.

Zheng Ruiqi R Weng Shuang S Xu Jianping J Li Zhuo Z Wang Yaru Y Aizimuaji Zulihumaer Z Ma Sheng S Zheng Linlin L Li Haiyang H Ying Wantao W Rong Weiqi W Xiao Ting T

Computational and structural biotechnology journal 20230705

As sorafenib is a first-line drug for treating advanced hepatocellular carcinoma, sorafenib resistance has historically attracted attention. However, most of this attention has been focused on a series of mechanisms related to drug resistance arising after sorafenib treatment. In this study, we used proteomic techniques to explore the potential mechanisms by which pretreatment factors affect sorafenib resistance. The degree of redundant pathway PI3K/AKT activation, biotransformation capacity, an ...[more]

PMID: 37520282

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Dataset Information

Autophagy and biotransformation affect sorafenib resistance in hepatocellular carcinoma

Publications

Autophagy and biotransformation affect sorafenib resistance in hepatocellular carcinoma.

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