AREG mediates transient hepatocellular carcinoma resistance to receptor tyrosine kinase inhibitors.

Amphiregulin (AREG) transiently mediates lenvatinib resistance in hepatocellular carcinoma (HCC) cells, enabling survival via EGFR activation and marking an early-resistant adaptive state.

• Why it matters: Lenvatinib resistance in HCC remains a major clinical challenge, and resistance is linked to dynamic multi-step adaptive processes that are not well mapped over time.
• What they did: Using multi-timepoint, multi-omics sampling, the study defined three adaptive states with state transitions and then used multi-omics plus functional validation to test AREG’s role.
• The result: AREG was sufficient and dominant to promote survival through EGFR activation, and pharmacological inhibition of the AREG–EGFR axis specifically targeted early-resistant cells, with AREG upregulation validated in additional replicate experiments and another HCC cell line.