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消除耐药性
诸平
据德国波恩大学(University of Bonn)2024年1月30日提供的消息(Elimination of drug resistance),波恩的研究人员发现,来自脂肪组织前体(fatty tissue precursors)的蛋白质是治疗失败的原因,并制定了解决策略。
尿路上皮癌(Urothelial carcinomas)是一种恶性肿瘤,例如,起源于膀胱和输尿管的上皮。它们仍然是欧洲最常见的癌症类型之一,尤其是在男性中。除早期诊断外,与预后相关的最重要因素是肿瘤的范围,这最终决定了治疗的侵入性和药物治疗方案。
一些研究表明,成纤维细胞生长因子受体家族(fibroblast growth factor receptor family简称FGFR)的遗传变化在包括尿路上皮癌在内的各种类型的癌症中起着核心作用。这些受体与各种成纤维细胞生长因子(fibroblast growth factors简称FGF)结合,FGF是调节细胞生长的信号蛋白。结合后,被激活的FGFRs,属于受体酪氨酸激酶(receptor tyrosine kinases)在细胞中启动信号级联反应。因此,FGFR信号通路参与细胞发育的许多核心过程,如生长、分化、迁移和细胞存活。
因此,除了一线治疗即首选药物之外,最近还使用了一种由酪氨酸激酶抑制剂(tyrosine kinase inhibitor)厄达非替尼(erdafitinib)组成的靶向癌症治疗,它可以阻断FGFR家族的所有亚型或其下游信号通路。“不幸的是,随后的临床试验显示,随着肿瘤进展,治疗迅速失败,因此受影响的患者只有暂时的生存获益,这是由于对厄达非替尼的耐药机制的发展,”波恩大学医院(University Hospital Bonn简称UKB)泌尿科和儿科泌尿科研究实验室主任阿卜杜拉·阿拉贾蒂(Abdullah Alajati)说。阿卜杜拉·阿拉贾蒂还在波恩大学进行研究。
HER3抗体治疗突破耐药机制(HER3 antibody therapy breaks through resistance mechanism)
因此,在研究潜在机制时,由阿卜杜拉·阿拉贾蒂博士领导的泌尿学研究实验室的团队主要关注肿瘤微环境的影响,即肿瘤的直接环境,它由各种成分组成,迄今为止几乎没有研究过。阿卜杜拉·阿拉贾蒂说:“我们发现一种特定的细胞类型,即前脂肪细胞(preadipocytes)也就是脂肪组织的前体细胞,在尿路上皮癌肿瘤细胞的耐药性发展中起着重要作用。”这些前体脂肪细胞分泌一种特殊的蛋白质,神经调节蛋白-1 (neuregulin-1简称NRG1)。作为受体酪氨酸蛋白激酶ErbB-3,也称为人表皮生长因子受体3 (human epidermal growth factor receptor 3简称HER3)最重要的配体之一,NRG1激活了这一替代信号通路。然而,这使得肿瘤细胞对厄达非替尼治疗不敏感。阿卜杜拉·阿拉贾蒂解释说:“我们能够证明关闭NRG1基因会导致细胞失去对厄达非替尼的抗性,这很清楚NRG1蛋白一定是这种抗性的中介。”
为了证实他们的假设,研究小组使用了抗体帕妥珠单抗(pertuzumab),这种抗体已经在临床实践中建立起来,可以阻止NRG1/HER3信号通路的激活。“有趣的是,同时使用厄达非替尼和帕妥珠单抗,肿瘤生长再次受到抑制,这在小鼠模型中也被证实对总体生存有积极影响,”UKB泌尿科和儿科泌尿科(Department of Urology and Pediatric Urology at the UKB)研究实验室的博士生萨娜·胡斯尼(Sana Hosni)说。
波恩大学的博士生维奥拉·基利安(Viola Kilian)补充说:“这意味着厄达非替尼耐药性可以通过额外阻断HER3信号传导而逆转。”研究小组希望这些研究结果和由此产生的假设将在进一步的研究,特别是临床研究中得到评估,以便在不久的将来能够在转移性尿路上皮癌患者的治疗中使用有效的联合疗法。由于NRG1/HER3信号通路在乳腺癌或卵巢癌等其他肿瘤实体中也起着重要作用,因此我们的研究结果也可能非常相关,”阿卜杜拉·阿拉贾蒂说。
上述介绍,仅供参考。欲了解更多信息,敬请注意浏览原文或者相关报道。
Sana Hosni; Viola Kilian; Niklas Klümper, Daniela Gabbia, Katharina Sieckmann, Dillon Corvino, Anja Winkler, Miriam Saponaro, Karin Woersdoerfer, Doris Schmidt, Oliver Hahn, Ilaria Zanotto, Marina Bertlich, Marieta Toma, Tobias Bald, Markus Eckstein, Michael Hölzel, Matthias Geyer, Manuel Ritter, Dagmar Wachten, Sara De Martin, Abdullah Alajati. Adipocyte precursor-derived NRG1 promotes resistance to FGFR inhibition in urothelial carcinoma. Cancer Research, 2024. DOI: 10.1158/0008-5472.can-23-1398. Pub Date: January 04 2024. https://doi.org/10.1158/0008-5472.can-23-1398
Aberrations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic urothelial cancer (mUC), and blocking the FGF/FGFR signaling axis is used as a targeted therapeutic strategy for treating patients. Erdafitinib is a pan-FGFR inhibitor that has recently been approved by the Food and Drug Administration for mUC with FGFR2/3 alterations. Although mUC patients show initial response to erdafitinib, acquired resistance rapidly develops. Here, we found that adipocyte precursors promoted resistance to erdafitinib in FGFR-dependent bladder and lung cancer in a paracrine manner. Moreover, neuregulin 1 (NRG1) secreted from adipocyte precursors was a mediator of erdafitinib resistance by activating human epidermal growth factor receptor 3 (ERBB3 also known as HER3) signaling, and knockdown of NRG1 in adipocyte precursors abrogated the conferred paracrine resistance. NRG1 expression was significantly downregulated in terminally differentiated adipocytes compared to their progenitors. Pharmacological inhibition of the NRG1/HER3 axis using pertuzumab reversed erdafitinib resistance in tumor cells in vitro and prolonged survival of mice bearing bladder cancer xenografts in vivo. Remarkably, data from single-cell RNA-sequencing revealed that NRG1 was enriched in platelet-derived growth factor receptor-A (PDGFRA) expressing inflammatory cancer-associated fibroblasts, which is also expressed on adipocyte precursors. Together, this work reveals a paracrine mechanism of anti-FGFR resistance in bladder cancer, and potentially other cancers, that is amenable to inhibition using available targeted therapies.
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