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首页> 外文期刊>Neoplasia: an international journal for oncology research >Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer
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Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer

机译：乙酰肝素酶在抗Lapatinib抗性脑转移乳腺癌中介导新的机制

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Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for targeting HPSE in brain metastatic breast cancer (BMBC). Lapatinib (Tykerb) is a small-molecule and dual inhibitor of human epidermal growth factor receptor1 and 2 (EGFR and HER2, respectively) which are both high-risk predictors of BMBC. It was approved by the US Food and Drug Administration for treatment of patients with advanced or metastatic breast cancer. However, its role is limited in BMBC whose response rates to lapatinib are significantly lower than those for extracranial metastasis. Because HPSE can affect EGFR phosphorylation, we examined Roneparstat, a non-anticoagulant heparin with potent anti-HPSE activity, to inhibit EGFR signaling pathways and BMBC onset using lapatinib-resistant clones generated from HER2-transfected, EGFR-expressing MDA-MB-231BR cells. Cell growth, EGFR pathways, and HPSE targets were assessed among selected clones in the absence or presence of Roneparstat and/or lapatinib. Roneparstat overcame lapatinib resistance by inhibiting pathways associated with EGFR tyrosine residues that are not targeted by lapatinib. Roneparstat inhibited the growth and BMBC abilities of lapatinib-resistant clones. A molecular mechanism was identified by which HPSE mediates an alternative survival pathway in lapatinib-resistant clones and is modulated by Roneparstat. These results demonstrate that the inhibition of HPSE-mediated signaling plays important roles in lapatinib resistance, and provide mechanistic insights to validate the use of Roneparstat for novel BMBC therapeutic strategies.
机译：乙肝素酶（HPSE）是主要的哺乳动物内糖苷酶和重要的致瘤，血管生成和血管转移分子。在具有殖民殖民化的最高致力的细胞中，始终检测到最高水平的HPSE活性，并强调靶向脑转移乳腺癌（BMBC）的治疗潜力。 Lapatinib（Tykerb）是人表皮生长因子受体1和2（EGFR和HER2）的小分子和双重抑制剂，这是BMBC的高风险预测因子。它被美国食品和药物管理局批准用于治疗先进或转移性乳腺癌的患者。然而，其作用在BMBC中受到限制，其对Lapatinib的反应率显着低于颅外转移的率。由于HPSE可以影响EGFR磷酸化，因此我们检查了一种具有有效的抗HPSE活性的非抗凝血剂肝素的Roneparstat，以抑制EGFR信号通路和BMBC发作，使用从HER2-转染的EGFA-MB-231BR产生的Lapatinib抗性克隆细胞。在roneparstat和/或rapatinib的缺失或存在下，在所选克隆中评估细胞生长，EGFR途径和HPSE靶标。 roneparstat通过抑制与Nuff酪氨酸残基相关的途径来克服Lapatinib阻力，所述酪氨酸残基与Lapatinib未靶向。 Roneparstat抑制了Lapatinib抗性克隆的生长和BMBC能力。鉴定了一种分子机制，通过该方法，HPSE介导抗胰岛抗克隆中的替代存活途径，并通过岩浆调节。这些结果表明，抑制HPSE介导的信号传导在Lapatinib电阻中起重要作用，并提供机械洞察，以验证roneparstat进行新型BMBC治疗策略的使用。

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