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Exosome-derived lnc-FAM72D-3 promotes lenvatinib resistance by remodeling hepatocellular carcinoma cytoskeleton via MBNL1/FAK axis

ABSTRACT: This study addresses a critical and unresolved issue in hepatocellular carcinoma treatment: the development of lenvatinib resistance. We provide compelling evidence that exosome-derived lnc-FAM72D-3 plays a pivotal role in promoting lenvatinib resistance by remodeling the cytoskeleton of hepatocellular carcinoma cells through the MBNL1/FAK axis. Simultaneously, through validation using both in vivo and in vitro models, we have firmly demonstrated that the combination therapy of FAK inhibitor and lenvatinib can significantly reverse the extent of lenvatinib resistance. Furthermore, the expression levels of lnc-FAM72D-3/MBNL1/FAK in clinically collected specimens from both lenvatinib-resistant and lenvatinib-sensitive patients were consistent with our results.

ORGANISM(S): Homo Sapiens

SUBMITTER: Zhicheng Yao

PROVIDER: PXD059707 | iProX | Fri Jan 10 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Abstract: Cancer-associated fibroblasts (CAFs) play an important role in the induction of chemo-resistance. The objectives of this study were to clarify the mechanism underlying CAF-mediated sorafenib/lenvatinib resistance and identify a novel therapeutic target to overcome resistance to sorafenib/lenvatinib in hepatocellular carcinoma (HCC). Methods: Whole transcriptome sequencing (WTS) data of nine pairs of CAFs and para-cancer-associated fibroblasts (PAFs) were analyzed to identify key molecules that induce resistance to tyrosine kinase inhibitors (TKIs). In vitro and in vivo experiments were performed to validate selected targets and related mechanisms. Plasma secreted phosphoprotein 1 (SPP1) expression levels prior to sorafenib/lenvatinib treatment as well as progression-free survival (PFS) and overall survival (OS) of an advanced HCC cohort (n=42) were evaluated using Kaplan–Meier analysis. Results: Co-culturing CAFs and HCC cells significantly reduced the responsiveness of HCC cells to sorafenib/lenvatinib, in vitro and in vivo. Systematic integrative analysis of the WTS data of CAFs/PAFs and publicly available gene expression data indicated that CAF-derived SPP1 (CAF-SPP1) was suitable for use as a candidate molecule to induce sorafenib/lenvatinib resistance. An evaluation of the mechanisms involved indicated that CAF-SPP1 increased phosphorylation of PKCɑ, which then activated rapidly accelerated fibrosarcoma (RAF)-extracellular signal-related kinase 1/2-signal transducer and activator of transcription 3 (STAT3) and phosophoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin kinase (mTOR) in HCC cells. SPP1 inhibitors reversed CAF-induced sorafenib/lenvatinib resistance in vitro and in vivo. Patients showing high plasma SPP1 prior to sorafenib/lenvatinib treatment exhibited significantly poor PFS (P=0.005) and OS (P=0.041). Conclusions: CAF-SPP1 enhances sorafenib/lenvatinib resistance in HCC by alternatively activating oncogenic pathways via PKCɑ phosphorylation. Inhibition of CAF-SPP1 may be utilized as a therapeutic strategy against TKI resistance in HCC. Plasma SPP1 level prior to TKI treatment shows potential as a promising biomarker for predicting sorafenib/lenvatinib response in advanced HCC patients.

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Exosome-derived lnc-FAM72D-3 promotes lenvatinib resistance by remodeling hepatocellular carcinoma cytoskeleton via MBNL1/FAK axis

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