A lenvatinib-resistance-derived transcriptional program identifies metabolic identity remodeling associated with unfavorable survival in hepatocellular carcinoma
Background: Metabolic adaptation is a recognized feature of therapeutic resistance in hepatocellular carcinoma (HCC), but it is unclear whether transcriptional states exposed during acquired resistance are restricted to drug adaptation or reflect broader aggressive tumor biology. We tested whether metabolic programs derived from a lenvatinib-resistance model identify a clinically adverse…
A study has uncovered a transcriptional program in hepatocellular carcinoma (HCC) that is linked to unfavorable survival outcomes after developing resistance to lenvatinib treatment. Researchers analyzed GSE186191, a dataset containing both parental and acquired lenvatinib-resistant Hep3B and Huh7 cells. They identified three key metabolic programs: MYC Targets V2, mTORC1 Signaling, and Fatty Acid Metabolism.
These programs were then tested in a cohort of 282 HCC patients, with 141 patients falling into each median-defined score group based on the integrated metabolic score.
The results showed that patients with high scores had significantly shorter overall survival (log-rank P=0.000419) compared to those with low scores. This association with mortality remained significant even after adjusting for age, sex, and stage indicators in the frozen model (HR 1.93, 95% CI 1.35-2.76; P=0.000350). Furthermore, in 327 primary tumors, the Fatty Acid Metabolism program was found to be strongly depleted in high-score tumors (NES -2.06; FDR).
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