2. Academic Validation
  3. Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma

Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma

  • Cell Death Dis. 2022 Aug 19;13(8):724. doi: 10.1038/s41419-022-05171-3.
Qi Sun  # 1,  Yujie Wang  # 2,  Hong Ji  # 3,  Xiaoting Sun 1 4 5,  Sisi Xie 1 6,  Longtian Chen 6,  Sen Li 1,  Weifan Zeng 1,  Ruibo Chen 1,  Qi Tang 1,  Ji Zuo 1,  Likun Hou 7,  Kayoko Hosaka 4,  Yongtian Lu 2,  Ying Liu 8,  Ying Ye 9,  Yunlong Yang 10
Affiliations

Affiliations

  • 1 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.
  • 2 Department of Otolaryngology, Shenzhen Key Laboratory of Nanozymes and Translational Cancer Research, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 518035, Shenzhen, Guangdong, China.
  • 3 Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
  • 5 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vison and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China.
  • 6 Longyan First Hospital Affiliated to Fujian Medical University, 364000, Longyan, Fujian, China.
  • 7 Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, P. R. China.
  • 8 Institute of Translational Medicine, Shanghai University, 99 Shangda Road, 200444, Shanghai, China. liuchanger1984@163.com.
  • 9 Department of Oral Implantology, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China. ying.ye@tongji.edu.cn.
  • 10 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China. yunlongyang@fudan.edu.cn.
  • # Contributed equally.
PMID: 35985991 DOI: 10.1038/s41419-022-05171-3
Abstract

Nasopharyngeal carcinoma (NPC) clinical trials show that antiangiogenic drugs (AADs) fail to achieve the expected efficacy, and combining AAD with chemoradiotherapy does not show superiority over chemoradiotherapy alone. Accumulating evidence suggests the intrinsic AAD resistance in NPC patients with poorly understood molecular mechanisms. Here, we describe NPC-specific FGF-2 expression-triggered, VEGF-independent angiogenesis as a mechanism of AAD resistance. Angiogenic factors screening between AAD-sensitive Cancer type and AAD-resistant NPC showed high FGF-2 expression in NPC in both xenograft models and clinical samples. Mechanistically, the FGF-2-FGFR1-MYC axis drove endothelial cell survival and proliferation as an alternative to VEGF-VEGFR2-MYC signaling. Genetic knockdown of FGF-2 in NPC tumor cells reduced tumor angiogenesis, enhanced AAD sensitivity, and reduced pulmonary metastasis. Moreover, lenvatinib, an FDA recently approved multi-kinase inhibitor targeting both VEGFR2/KDR/Flk-1 and FGFR1, effectively inhibits the tumor vasculature, and exhibited robust anti-tumor effects in NPC-bearing nude mice and humanized mice compared with an agent equivalent to bevacizumab. These findings provide mechanistic insights on FGF-2 signaling in the modulation of VEGF pathway activation in the NPC microenvironment and propose an effective NPC-targeted therapy by using a clinically available drug.

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