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Hepatology International

Erschienen in:

31.07.2021 | Original Article

Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma

verfasst von: David Wai Meng Tai, Thi Bich Uyen Le, Aldo Prawira, Rebecca Zhi Wen Ho, Hung Huynh

Erschienen in: Hepatology International | Ausgabe 5/2021

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Abstract

Background

Hepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. The overexpression of fibroblast growth factor (FGF) receptors (FGFRs) signaling cascade has been shown to contribute to tumorigenesis, metastasis, and poor prognosis in HCC. Therefore, targeted inhibition of the FGF/FGFR cascade may represent a new treatment strategy for HCC patients.

Methods

HCC patient-derived xenograft (PDX) models were implanted into either severe combined immunodeficient (SCID) or CD34+hu-NSG (humanized) mice and subsequently treated with vehicle, infigratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of infigratinib and FGF401. Tumor progressions, overall survival of mice, lung metastasis, and drug resistance were monitored, and samples collected at the end of the treatment cycle were subjected to Western blot analyses and immunohistochemistry.

Results

HCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and infigratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination infigratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination significantly increased the infiltration of B cells, macrophages, CD8+ T cells, and CD4+ T cells associated with granzyme-B-mediated apoptosis, delayed onset of resistance, and inhibited metastasis by potently inhibiting several critical signaling pathways involved in proliferation and metastasis.

Conclusions

Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials.

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Titel: Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma
verfasst von: David Wai Meng Tai
Thi Bich Uyen Le
Aldo Prawira
Rebecca Zhi Wen Ho
Hung Huynh
Publikationsdatum: 31.07.2021
Verlag: Springer India
Erschienen in: Hepatology International / Ausgabe 5/2021
Print ISSN: 1936-0533
Elektronische ISSN: 1936-0541
DOI: https://doi.org/10.1007/s12072-021-10212-8

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Abstract

Background

Methods

Results

Conclusions

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