Department I of Internal Medicine, University Hospital Cologne, Kerpener Straße 62, 50937, Cologne, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch Straße 21, 50931, Cologne, Germany.
Oncogene. 2018 Oct;37(42):5682-5693. doi: 10.1038/s41388-018-0380-3. Epub 2018 Jul 3.
FGFR1 amplification has been found in 15% of patients with breast cancer and has been postulated as a promising marker to predict response against FGFR inhibitors. However, early phase clinical trials of selective FGFR inhibitors demonstrated only limited efficacy in FGFR1-amplified breast cancer patients. We found that BGJ398, an FGFR inhibitor, effectively inhibited phosphorylation of FGFR1 and MEK/ERK signaling in FGFR1-amplified breast cancer without affecting tumor cell proliferation. However, FGFR1 knockout inhibited tumor angiogenesis in vivo. We unraveled that FGFR1 regulates the secretion of the proangiogenic vascular endothelial growth factor (VEGF) in a MAPK-dependent manner. We further found that FGF-FGFR1 signaling induces an autocrine activation of VEGF-VEGFR1 pathway that again amplifies VEGF secretion via VEGF-VEGFR1-AKT signaling. Targeting both VEGFR1 and FGFR1 resulted in synergistic anti-angiogenic treatment effects in vivo. We thus postulate synergistic treatment effects in FGFR1/VEGFR1-positive breast cancer patients by dual targeting of FGFR and VEGFR.
FGFR1 扩增已在 15%的乳腺癌患者中被发现，并被推测为预测 FGFR 抑制剂反应的有前途的标志物。然而，选择性 FGFR 抑制剂的早期临床试验仅在 FGFR1 扩增的乳腺癌患者中显示出有限的疗效。我们发现，FGFR 抑制剂 BGJ398 可有效抑制 FGFR1 磷酸化和 MEK/ERK 信号通路，而不影响肿瘤细胞增殖。然而，FGFR1 敲除抑制了体内肿瘤血管生成。我们揭示了 FGFR1 通过 MAPK 依赖性方式调节促血管生成血管内皮生长因子 (VEGF) 的分泌。我们进一步发现，FGF-FGFR1 信号诱导 VEGF-VEGFR1 途径的自分泌激活，该途径通过 VEGF-VEGFR1-AKT 信号再次放大 VEGF 的分泌。靶向 VEGFR1 和 FGFR1 可在体内产生协同的抗血管生成治疗效果。因此，我们推测通过双重靶向 FGFR 和 VEGFR，可在 FGFR1/VEGFR1 阳性乳腺癌患者中产生协同治疗效果。
