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. 2024 Dec;47(6):2439-2460.
doi: 10.1007/s13402-024-01032-7. Epub 2024 Dec 24.

GALNT6 drives lenvatinib resistance in hepatocellular carcinoma through autophagy and cancer-associated fibroblast activation

Peiling Zhang #  1   2 , Shiping Chen #  1   2 , Jialiang Cai #  1   2 , Lina Song  1   2 , Bing Quan  1   2 , Jinglei Wan  1 , Guiqi Zhu  1   3   4 , Biao Wang  5 , Yi Yang  5 , Zhengjun Zhou  1   2 , Tao Li  6 , Zhi Dai  7   8
Affiliations

GALNT6 drives lenvatinib resistance in hepatocellular carcinoma through autophagy and cancer-associated fibroblast activation

Peiling Zhang et al. Cell Oncol (Dordr). 2024 Dec.

Abstract

Background: Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited treatment options. Lenvatinib, a tyrosine kinase inhibitor, has shown promise but is often undermined by the development of drug resistance.

Methods: Utilizing high-throughput sequencing, we investigated the molecular mechanisms underlying lenvatinib resistance in HCC cells, with a focus on metabolic pathways. Key genes, including GALNT6, were validated through quantitative real-time PCR. The effects of GALNT6 knockdown on lenvatinib sensitivity were examined in vitro and in vivo. O-GalNAc glycosylation was assessed using Vicia Villosa Lectin. Immune cell infiltration and interactions were analyzed in the TCGA-LIHC cohort, with further validation by Western blotting and immunohistochemistry.

Results: Our findings indicate that lenvatinib resistance in HCC is driven by the mucin-type O-glycosylation pathway, with GALNT6 playing a critical role. Knockdown of GALNT6 led to reduced O-GalNAc glycosylation, including the modification of LAPTM5, resulting in decreased LAPTM5 activity and autophagy inhibition. Additionally, GALNT6 silencing disrupted the PDGFA-PDGFRB axis, impairing the activation of cancer-associated fibroblasts (CAFs) and reducing their secretion of SPP1, which collectively diminished lenvatinib resistance.

Conclusions: GALNT6 is integral to the resistance mechanisms against lenvatinib in HCC by modulating autophagy and CAF activation. Targeting GALNT6 offers a promising strategy to enhance lenvatinib efficacy and improve therapeutic outcomes in HCC.

Keywords: CAFs; GALNT6; LAPTM5; Lenvatinib resistance; Mucin-type O-glycosylation.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with the guidelines of the Animal Experiment Ethics Committee of Zhongshan Hospital, Fudan University, and received ethical approval. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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