What question did this study set out to answer?

This research aims to identify genomic alterations linked to lenvatinib resistance in hepatocellular carcinoma.

April 5, 2026

Abstract 5460: Elucidation of breakage-fusion-bridge (BFB)-mediated EGFR amplification in lenvatinib-resistant hepatocellular carcinoma.

Key Points

This research aims to identify genomic alterations linked to lenvatinib resistance in hepatocellular carcinoma.
Established a lenvatinib-resistant HCC cell line (Huh7) by gradual exposure to lenvatinib.
Performed whole genome sequencing (WGS) and whole transcriptome sequencing (WTS).
Conducted comparative genomic analysis between sensitive and resistant cell lines.
Utilized breakpoint analysis (LUMPY) to identify structural variations indicating breakage-fusion-bridge cycles.
EGFR copy number increased from 6 to 21 copies in resistant cells.
Activation of the EGFR-PAK2-ERK5 pathway was observed, indicating resistance mechanisms.
Combined treatment with lenvatinib and erlotinib decreased cell viability and restored sensitivity.
Patients with high EGFR levels showed shorter progression-free survival when treated with lenvatinib.

Abstract

Abstract Lenvatinib, a multi-targeted tyrosine kinase inhibitor, is widely used as a first-line therapy for patients with immunotherapy-ineligible hepatocellular carcinoma (HCC). However, its clinical benefit is often compromised by the development of resistance. Understanding the genomic alterations driving resistance is critical to improving therapeutic outcomes in HCC. In this study, a lenvatinib-resistant HCC cell line, Huh7, was established by exposing parental sensitive cells to increasing concentrations of lenvatinib. To elucidate the mechanisms underlying drug resistance, short- and long-read whole genome sequencing (WGS), whole transcriptome sequencing (WTS), and western blot were performed. Comparative analysis of genomic alterations between parental and resistant cells revealed marked differences in copy number (CN) profiles. In resistant cells, EGFR showed the most prominent CN gain, increasing from 6 to 21 copies. Detailed breakpoint analysis utilizing LUMPY identified fold-back inversions that directly corresponded with genomic locations exhibiting significant CN alterations, indicative of the hallmark features of breakage-fusion-bridge (BFB) cycles. These findings were confirmed by Sniffles-based long-read SV calling. Transcriptomic and protein-level analyses using WTS and Western blotting, respectively, showed increased EGFR expression. Gene set enrichment analysis showed significant enrichment of ERBB and MAPK pathways. Mechanistically, activation of the EGFR-PAK2-ERK5 axis was observed, suggesting that lenvatinib-induced blockade of VEGFR/FGFR promotes a bypass survival signal through EGFR downstream pathways. Combined treatment with lenvatinib and erlotinib, an EGFR inhibitor, reduced viability and restored sensitivity. Clinically, lenvatinib-treated HCC patients with high EGFR immunohistochemistry scores exhibited shorter progression-free survival, and public HCC cell line datasets consistently showed poor responses in EGFR-amplified cells. In conclusion, our findings suggest BFB-driven EGFR amplification as a key structural and functional driver of lenvatinib resistance in HCC. Lenvatinib combined with an EGFR inhibitor may offer a treatment option for patients with HCC exhibiting elevated EGFR expression. Citation Format: JungHyun (Jenny) Kim, Ji Young Kim, Hyeonu Yang, Sang Yun Ha, Han-Na Kim, Hoon Kim, Yeup Yoon, Wonseok Kang. Elucidation of breakage-fusion-bridge (BFB)-mediated EGFR amplification in lenvatinib-resistant hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5460.

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