Lenvatinib Targeting Mechanisms in Hepatocellular Carcinoma

Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor approved as a first-line agent in advanced hepatocellular carcinoma (HCC). It exerts antitumour effects principally via blockade of vascular endothelial growth factor and fibroblast growth factor receptor signalling, suppressing angiogenesis and tumour proliferation. However, treatment efficacy is limited by both intrinsic and acquired resistance, driven by adaptive kinase rewiring, stabilisation of hypoxia-responsive transcription factors and expansion of cancer stem cell populations. Mechanisms such as upregulation of cyclin-dependent kinase 6, activation of PDGFRA- or EGFR-mediated prosurvival cascades, and engagement of ubiquitin-dependent pathways contribute to a refractory phenotype. Emerging strategies that combine lenvatinib with inhibitors targeting CDK6, deubiquitinases, PDGFRA or immune checkpoints have shown preclinical synergy. Moreover, patient-derived organoid pharmacogenomics and proteome-wide profiling have yielded predictive biomarkers and informed combination regimens poised to enhance personalised therapy in HCC.

Research from Nature Portfolio

Recent studies have employed chemoproteomic and kinase profiling to elucidate nongenetic resistance to lenvatinib. Broad-spectrum kinome mapping in resistant HCC models revealed a marked increase in CDK6 expression driven by ERK/YAP1 signalling. Non-canonical CDK6 binding to GSK3β was shown to activate Wnt/β-catenin pathways and enrich liver cancer stem cells. Combined inhibition of CDK6 using palbociclib or proteolysis-targeting chimaeras alongside lenvatinib not only reversed resistance but also favourably remodelled the tumour immune microenvironment, demonstrating potent synergistic antitumour activity in vitro and in vivo.

Lenvatinib Targeting Mechanisms in Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in lenvatinib targeting mechanisms in hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Receptor tyrosine kinase inhibitor: A small molecule that interferes with the kinase domains of receptor tyrosine kinases, preventing phosphorylation-mediated signal transduction.

Angiogenesis: Formation of new blood vessels from pre-existing vasculature, a process often co-opted by tumours to secure nutrients and oxygen.

Cancer stem cells: A sub-population within tumours endowed with self-renewal capacity and multidrug resistance, implicated in disease recurrence.

Ubiquitination: Attachment of ubiquitin molecules to a protein substrate, typically marking it for proteasomal degradation or altering its cellular function.

Organoid: A three-dimensional cell culture system derived from patient tissue that recapitulates organ-specific architecture and function.

Proteolysis-targeting chimaera: A bifunctional molecule that recruits an E3 ubiquitin ligase to a target protein, inducing its ubiquitination and subsequent degradation.

References

1. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Medicine (2018).
2. Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma. Nature Communications (2023).
3. The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma. Signal Transduction and Targeted Therapy (2024).
4. Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer. Cancer Cell (2024).
5. Targeted inhibition of PDGFRA with avapritinib, markedly enhances lenvatinib efficacy in hepatocellular carcinoma in vitro and in vivo: clinical implications. Journal of Experimental & Clinical Cancer Research (2025).
6. Inhibition of EGFR overcomes acquired lenvatinib resistance driven by STAT3-ABCB1 signaling in hepatocellular carcinoma. Cancer Research (2022).
7. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLOS ONE (2019).
8. Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance. Cell Death Discovery (2021).