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HIF-1 signaling contributes to lenvatinib resistance in patient-derived HCC organoids.

Yongye Huang·Zhu Ai·Senmiao Huang
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Abstract

Resistance to lenvatinib remains an important limitation in hepatocellular carcinoma treatment. Six patient-derived organoid lines were established and classified as sensitive or resistant according to ex vivo drug responses, retaining histological and immunophenotypic features of matched parental tumors. Resistant organoids showed unchanged ATP activity, whereas sensitive ones exhibited pronounced morphological changes and reduced ATP activity at higher concentrations. Transcriptome sequencing identified 408 upregulated and 269 downregulated genes in resistant versus sensitive organoids, with HIF-1 signaling among altered pathways. In resistant organoids, lenvatinib increased HIF-1α, ANGPT2, and HK3 mRNA, whereas comparable changes were not detected in sensitive organoids. KC7F2 reduced these transcripts and further decreased ATP activity when combined with lenvatinib. In organoid-derived xenografts, this combination suppressed tumor growth and HIF-1 target expression more than lenvatinib alone, indicating HIF-1 signaling contributes to the resistant phenotype and its inhibition may enhance response.

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Drug resistanceHIF-1 signaling pathwayHepatocellular carcinomaLenvatinibOrganoidJournal Article

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BibTeXRIS

Yongye Huang, Zhu Ai, Senmiao Huang. 2026-09-04. HIF-1 signaling contributes to lenvatinib resistance in patient-derived HCC organoids.. https://doi.org/10.1016/j.ygeno.2026.111310

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Futibatinib after non-covalent FGFR inhibitors in FGFR2-rearranged intrahepatic cholangiocarcinoma: clinical activity and resistance patterns.

PURPOSE: The optimal sequencing of non-covalent and covalent FGFR inhibitors in FGFR2-rearranged intrahepatic cholangiocarcinoma (iCCA) remains undefined. Futibatinib, an irreversible FGFR1-4 inhibitor, may retain activity in the setting of acquired resistance to non-covalent FGFR inhibitors, but data on the patterns of acquired alterations are limited. METHODS: We conducted a retrospective multicenter study across three European centers including patients with advanced FGFR2-rearranged iCCA treated with futibatinib after progression on non-covalent FGFR inhibitors. Clinical outcomes and safety were evaluated. Available genomic profiling at progression was analyzed to characterize resistance mechanisms and their association with outcomes. RESULTS: Sixteen patients were included. Median progression-free survival (mPFS) with prior non-covalent FGFR inhibitors was 10.2 months (95% CI 7.0-15.5), with an objective response rate (ORR) of 60.0%. Among patients with post-progression genomic profiling (n = 11), all harbored FGFR2 resistance mutations, with polyclonal alterations (≥2) in 45.5%. A higher burden of FGFR2 mutations and the presence of co-alterations were associated with shorter mPFS on non-covalent inhibitors. Futibatinib was administered at a median of fourth-line therapy. ORR was 31.3% and disease control rate was 50.0%. Median PFS and overall survival were 4.5 months (95% CI 2.0-9.1) and 9.9 months (95% CI 5.7-not reached), respectively. Notably, outcomes with futibatinib were independent of the number of acquired FGFR2 resistance mutations, and the adverse impact of co-alterations appeared attenuated. Safety was consistent with the known profile. CONCLUSIONS: Futibatinib demonstrates clinically meaningful activity after progression on non-covalent FGFR inhibitors, supporting its use in FGFR2-rearranged iCCA, including in the post-non-covalent inhibitor setting. The distinct resistance patterns provide a biological rationale for the continued efficacy of covalent FGFR inhibition. Prospective studies incorporating longitudinal molecular profiling are needed to optimize treatment sequencing.

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