Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer
Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer
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DOI：
10.1677/erc.1.01297
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发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Nicholson, Robert I.
中科院分区：
文献类型：
--
作者：
Hiscox, Stephen;Morgan, L.;Nicholson, Robert I.
内分泌治疗是激素受体阳性乳腺癌的首选治疗方法。然而，由于耐药性的产生，抗激素药物如他莫昔芬的疗效有限，最终导致疾病进展和患者死亡。使用体外细胞模型的抗激素抵抗，我们以前已经证明，改变的生长因子信号有助于内分泌不敏感的表型。值得注意的是，我们最近的研究表明，乳腺癌患者内分泌抵抗的获得伴随着显著增强的迁移和侵袭性表型。此外，尽管最初处于生长抑制阶段，但使用抗生长因子单一疗法的治疗干预再次导致耐药状态的发展和侵袭性表型的进一步增强。使用双重特异性的Src/Abl激酶抑制剂AZD0530，我们强调了Src激酶在促进伴随抗激素和抗生长因子耐药性的侵袭性表型中的核心作用。重要的是，Src抑制剂与抗生长因子疗法联合使用似乎是相加的，对细胞的生长、迁移和侵袭产生显著的抑制作用，并最终防止耐药表型的出现。这些观察表明，抑制Src活性可能提供一种新的治疗干预策略，特别是当用作内分泌抵抗型乳腺疾病的佐剂时，有可能延缓或防止随后获得抗生长因子治疗的耐药性。
Endocrine therapy is the treatment of choice in hormone receptor-positive breast cancer. However, the effectiveness of anti-hormone drugs, such as tamoxifen, is limited because of the development of resistance, ultimately leading to disease progression and patient mortality. Using in vitro cell models of anti-hormone resistance, we have previously demonstrated that altered growth factor signalling contributes to an endocrine insensitive phenotype. Significantly, our recent studies have revealed that the acquisition of endocrine resistance in breast cancer is accompanied by a greatly enhanced migratory and invasive phenotype. Furthermore, therapeutic intervention using anti-growth factor monotherapies, despite an initial growth suppressive phase, again results in the development of a resistant state and a further augmentation of their invasive phenotype.Using the dual specific Src/Abl kinase inhibitor, AZD0530, we have highlighted a central role for Src kinase in promoting the invasive phenotype that accompanies both anti-hormone and antigrowth factor resistance. Importantly, the use of Src inhibitors in combination with anti-growth factor therapies appears to be additive, producing a marked inhibitory effect on cell growth, migration and invasion and ultimately prevents the emergence of a resistant phenotype. These observations suggest that the inhibition of Src activity may present a novel therapeutic intervention strategy, particularly when used as an adjuvant in endocrine-resistant breast disease, with the potential to delay or prevent the acquisition of subsequent resistance to anti-growth factor therapies.