Targeted inhibition of PDGFRA with avapritinib, markedly enhances lenvatinib efficacy in hepatocellular carcinoma in vitro and in vivo: clinical implications.

Background

Lenvatinib, a tyrosine kinase receptor inhibitor, has emerged as a frontline therapeutic strategy for the management of advanced hepatocellular carcinoma (HCC). However, the modest response rate observed with lenvatinib and the rapid emergence of chemoresistance highlight the urgent need to elucidate the underlying molecular mechanisms. Herein we aimed at identifying the molecular mechanisms underlying lenvatinib resistance in HCC and investigated the efficacy of targeted combination therapies to surmount this chemoresistance.

Methods

We utilized CRISPR/Cas9 gene knockout screening combined with transcriptome sequencing of lenvatinib-resistant HCC cell lines to identify resistance-associated genes. PDGFRA overexpression was validated in human lenvatinib-resistant HCC cells. We further corroborated the in vitro and in vivo role of PDGFRA in lenvatinib resistance using a PDGFRA inhibitor, avapritinib, employing a mouse orthotopic HCC model, patient-derived organoids (PDO), and patient-derived xenografts (PDX). The association between PDGFRA expression and patient prognosis was also assessed. Mechanistic studies were conducted to elucidate the signaling pathways contributing to lenvatinib resistance mediated by PDGFRA.

Results

PDGFRA overexpression was identified as a key determinant of lenvatinib-resistance in HCC cells. Consistently, ectopic PGDGFRA overexpression conferred lenvatinib resistance upon HCC cells. Treatment with the PDGFRA inhibitor avapritinib sensitized HCC cells to lenvatinib in mouse orthotopic HCC, PDO, and PDX models. Increased PDGFRA expression was correlated with poor prognosis in HCC patients. Mechanistic studies revealed that lenvatinib treatment or PDGFRA overexpression promoted HCC resistance through the PTEN/AKT/GSK-3β/β-catenin signaling pathway.

Conclusions

Our findings demonstrate that PDGFRA overexpression mediates lenvatinib resistance in HCC and that targeting PDGFRA with avapritinib, surmounts this resistance. Furthermore, the PTEN/AKT/GSK-3β/β-catenin pathway was implicated in lenvatinib resistance, providing a potential therapeutic strategy for HCC patients displaying lenvatinib resistance. Further clinical studies are warranted to validate these findings and to explore the clinical application of PDGFRA-targeted therapies in HCC treatment.

COI Statement

Declarations. Ethics approval and consent to participate: The tissue samples used in this study were obtained from Mengchao Hepatobiliary Hospital of Fujian Medical University. Sample collection and use were approved by Medical Ethics Committee of Mengchao Hepatobiliary Hospital of Fujian Medical University (2022_018_01). Meanwhile, informed consent was provided by the patients. All animal experiments were conducted in strict accordance with protocols approved by the Animal Ethics Committee of Mengchao Hepatobiliary Hospital of Fujian Medical University (MCHH-AEC-2022-12). Consent for publication: The content of this manuscript has not been previously published. Competing interests: The authors declare no competing interests.

References:

• Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014:638747.
• Guo J, Zhao J, Xu Q, Huang D. Resistance of lenvatinib in hepatocellular carcinoma. Curr Cancer Drug Targets. 2022;22(11):865–78.
• You Q, Li R, Yao J, Zhang YC, Sui X, Xiao CC, et al. Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity. Med Oncol. 2024;41(3):75.
• Buttell A, Qiu W. The action and resistance mechanisms of lenvatinib in liver cancer. Mol Carcinog. 2023;62(12):1918–34.
• Huang M, Long J, Yao Z, Zhao Y, Zhao Y, Liao J, et al. METTL1-Mediated m7G tRNA modification promotes lenvatinib resistance in hepatocellular carcinoma. Cancer Res. 2023;83(1):89–102.