Inhibition of FAK kinase activity preferentially targets cancer stem cells.
Inhibition of FAK kinase activity preferentially targets cancer stem cells.
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DOI：
10.18632/oncotarget.18517
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发表时间：
2017-08-01
期刊：
影响因子：
--
通讯作者：
Weaver DT
中科院分区：
文献类型：
--
作者：
Kolev VN;Tam WF;Wright QG;McDermott SP;Vidal CM;Shapiro IM;Xu Q;Wicha MS;Pachter JA;Weaver DT
由于癌症干细胞（CSCs）与化疗耐药、转移和肿瘤复发有关，因此靶向治疗CSCs有望解决这些癌症治疗的临床挑战。VS-4718和VS-6063是局灶黏着激酶（FAK）的有效抑制剂，FAK是一种非受体酪氨酸激酶，介导整合素和生长因子受体传递的细胞信号。我们在这里报道，通过细胞系模型和手术切除的原发乳腺癌体外培养标本的一组正交CSC试验，证明了VS-4718或VS-6063对FAK激酶活性的抑制优先靶向CSC。口服VS-4718或VS-6063给携带三阴性乳腺癌（TNBC）异种移植模型的小鼠，可显著降低肿瘤中CSCs的比例，这可以通过重新植入肿瘤后降低肿瘤启动能力来证明，从而限制了从这些肿瘤中制备的细胞的稀释度。相比之下，细胞毒性化疗药物，紫杉醇和卡铂，对CSCs富集，与先前的报道一致，这些细胞毒性药物优先针对非CSCs。重要的是，VS-4718和VS-6063在体外减弱化疗诱导的CSCs富集，并延迟化疗停止后的肿瘤再生。FAK与Wnt/β-catenin通路之间存在有趣的串扰，其中FAK抑制通过降低β-catenin的酪氨酸654磷酸化来阻断β-catenin的激活。此外，β-catenin的组成型活性突变形式通过FAK抑制逆转了CSCs的优先靶向，这表明这种靶向至少部分是通过减弱β-catenin的激活来介导的。FAK抑制剂对癌症干细胞的优先靶向为临床开发旨在增加癌症患者持久反应的FAK抑制剂提供了理论依据。
Because cancer stem cells (CSCs) have been implicated in chemo-resistance, metastasis and tumor recurrence, therapeutic targeting of CSCs holds promise to address these clinical challenges to cancer treatment. VS-4718 and VS-6063 are potent inhibitors of focal adhesion kinase (FAK), a non-receptor tyrosine kinase that mediates cell signals transmitted by integrins and growth factor receptors. We report here that inhibition of FAK kinase activity by VS-4718 or VS-6063 preferentially targets CSCs, as demonstrated by a panel of orthogonal CSC assays in cell line models and surgically resected primary breast tumor specimens cultured ex vivo. Oral administration of VS-4718 or VS-6063 to mice bearing xenograft models of triple-negative breast cancer (TNBC) significantly reduced the proportion of CSCs in the tumors, as evidenced by a reduced tumor-initiating capability upon re-implantation in limiting dilutions of cells prepared from these tumors. In contrast, the cytotoxic chemotherapeutic agents, paclitaxel and carboplatin, enriched for CSCs, consistent with previous reports that these cytotoxic agents preferentially target non-CSCs. Importantly, VS-4718 and VS-6063 attenuated the chemotherapy-induced enrichment of CSCs in vitro and delayed tumor regrowth following cessation of chemotherapy. An intriguing crosstalk between FAK and the Wnt/β-catenin pathway was revealed wherein FAK inhibition blocks β-catenin activation by reducing tyrosine 654 phosphorylation of β-catenin. Furthermore, a constitutively active mutant form of β-catenin reversed the preferential targeting of CSCs by FAK inhibition, suggesting that this targeting is mediated, at least in part, through attenuating β-catenin activation. The preferential targeting of cancer stem cells by FAK inhibitors provides a rationale for the clinical development of FAK inhibitors aimed to increase durable responses for cancer patients.
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影响因子：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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