David Wai Meng Tai1, Thi Bich Uyen Le2, Aldo Prawira2, Rebecca Zhi Wen Ho2, Hung Huynh3. 1. Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore. 2. Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore. 3. Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore. cmrhth@nccs.com.sg.
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.
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.
Authors: Stephen L Chan; Martin Schuler; Yoon-Koo Kang; Chia-Jui Yen; Julien Edeline; Su Pin Choo; Chia-Chi Lin; Takuji Okusaka; Karl-Heinz Weiss; Teresa Macarulla; Stéphane Cattan; Jean-Frederic Blanc; Kyung-Hun Lee; Michela Maur; Shubham Pant; Masatoshi Kudo; Eric Assenat; Andrew X Zhu; Thomas Yau; Ho Yeong Lim; Jordi Bruix; Andreas Geier; Carmen Guillén-Ponce; Angelica Fasolo; Richard S Finn; Jia Fan; Arndt Vogel; Shukui Qin; Markus Riester; Vasiliki Katsanou; Monica Chaudhari; Tomoyuki Kakizume; Yi Gu; Diana Graus Porta; Andrea Myers; Jean-Pierre Delord Journal: J Exp Clin Cancer Res Date: 2022-06-02