Kitowska Kamila, Gorska-Arcisz Monika, Antoun Dima, Zarczynska Izabela, Czaplinska Dominika, Szczepaniak Adrian, Skladanowski Andrzej C, Wieczorek Maciej, Stanczak Aleksandra, Skupinska Monika, Sadej Rafal
Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Gdansk, Poland.
Innovative Drugs R&D Department, Celon Pharma, Lomianki/Kielpin, Poland.
Front Oncol. 2021 Apr 7;11:633410. doi: 10.3389/fonc.2021.633410. eCollection 2021.
Deregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result of amplification, chromosomal translocation, or mutations, is involved in both initiation and progression of a wide range of human cancers. Clinical data demonstrating the dependence of cancer cells on FGFRs signaling clearly indicate these receptors as the molecular targets of anti-cancer therapies. Despite the increasing number of tyrosine kinase inhibitors (TKIs) being investigated in clinical trials, acquired resistance to these drugs poses a serious therapeutic problem. In this study, we focused on a novel pan-FGFR inhibitor-CPL304110, currently being investigated in phase I clinical trials in adults with advanced solid malignancies. We analyzed the sensitivity of 17 cell lines derived from cancers with aberrant FGFR signaling, i.e. non-small cell lung cancer, gastric and bladder cancer to CPL304110. In order to explore the mechanism of acquired resistance to this FGFR inhibitor, we developed from sensitive cell lines their variants resistant to CPL304110. Herein, for the first time we revealed that the process of acquired resistance to the novel FGFR inhibitor was associated with increased expression of MET in lung, gastric, and bladder cancer cells. Overexpression of MET in NCI-H1703, SNU-16, RT-112 cells as well as treatment with HGF resulted in the impaired response to inhibition of FGFR activity. Moreover, we demonstrated that cells with acquired resistance to FGFR inhibitor as well as cells overexpressing MET displayed enhanced migratory abilities what was accompanied with increased levels of Pyk2 expression. Importantly, inhibition of both MET and Pyk2 activity restored sensitivity to FGFR inhibition in these cells. Our results demonstrate that the HGF/MET-Pyk2 signaling axis confers resistance to the novel FGFR inhibitor, and this mechanism is common for lung, gastric, and bladder cancer cells. Our study suggests that targeting of MET/Pyk2 could be an approach to overcome resistance to FGFR inhibition.
由于扩增、染色体易位或突变导致成纤维细胞生长因子受体（FGFRs）信号传导失调，参与了多种人类癌症的发生和发展。临床数据表明癌细胞对FGFRs信号传导的依赖性，清楚地表明这些受体是抗癌治疗的分子靶点。尽管在临床试验中研究的酪氨酸激酶抑制剂（TKIs）数量不断增加，但对这些药物的获得性耐药构成了严重的治疗问题。在本研究中，我们聚焦于一种新型泛FGFR抑制剂——CPL304110，目前正在对患有晚期实体恶性肿瘤的成人进行I期临床试验。我们分析了17种源自FGFR信号异常的癌症（即非小细胞肺癌、胃癌和膀胱癌）的细胞系对CPL304110的敏感性。为了探究对这种FGFR抑制剂获得性耐药的机制，我们从敏感细胞系中培育出对CPL304110耐药的变体。在此，我们首次揭示，对新型FGFR抑制剂获得性耐药的过程与肺癌、胃癌和膀胱癌细胞中MET表达增加有关。在NCI-H1703、SNU-16、RT-112细胞中MET的过表达以及用HGF处理导致对FGFR活性抑制的反应受损。此外，我们证明对FGFR抑制剂获得性耐药的细胞以及过表达MET的细胞表现出增强的迁移能力，同时伴有Pyk2表达水平的增加。重要的是，抑制MET和Pyk2活性可恢复这些细胞对FGFR抑制的敏感性。我们的结果表明，HGF/MET-Pyk2信号轴赋予了对新型FGFR抑制剂的耐药性，并且这种机制在肺癌、胃癌和膀胱癌细胞中是常见的。我们的研究表明，靶向MET/Pyk2可能是克服对FGFR抑制耐药的一种方法。
