Salem Israa, Alsalahi Manal, Chervoneva Inna, Aburto Lucy D, Addya Sankar, Ott Gregory R, Ruggeri Bruce A, Cristofanilli Massimo, Fernandez Sandra V
Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
Breast Cancer Res. 2016 Mar 24;18(1):37. doi: 10.1186/s13058-016-0694-4.
Inflammatory breast cancer (IBC) is an aggressive type of advanced breast cancer with a poor prognosis. We recently found that focal adhesion kinase 1 (FAK1) is upregulated and phosphorylated (active) in IBC. In this study, we investigated the effect of CEP-37440, a dual inhibitor of FAK1 and anaplastic lymphoma kinase (ALK), using human IBC cell lines and preclinical models of IBC.
Cell proliferation assays were performed in the presence of several concentrations of CEP-37440 using IBC and triple-negative breast cancer non-IBC cell lines. In vitro, we studied the expression of total FAK1, phospho-FAK1 (Tyr 397), total ALK and phospho-ALK (Tyr 1604). In vivo, we tested CEP-37440 using FC-IBC02, SUM149, and SUM190 IBC xenograft mouse models.
CEP-37440 at low concentration decreased the proliferation of the IBC cell lines FC-IBC02, SUM190, and KPL4, while not affecting the proliferation of normal breast epithelial cells. At higher concentration, CEP-37440 was also able to inhibit the proliferation of the IBC cell line MDA-IBC03 and the triple-negative non-IBC cell lines MDA-MB-231 and MDA-MB-468; the IBC cell line SUM149 showed a slight response to the drug. CEP-37440 decreased the cell proliferation of FC-IBC02, SUM190, and KPL4 by blocking the autophosphorylation kinase activity of FAK1 (Tyr 397). None of the cells evaluated expressed ALK. In vivo, after 7 weeks of CEP-37440 treatment, the SUM190, FC-IBC02, and SUM149 breast tumor xenografts were smaller in mice treated with 55 mg/kg bid CEP-37440 compared to the controls; the tumor growth inhibition (TGI) was 79.7 %, 33 %, and 23 %, respectively. None of the FC-IBC02 breast xenografts mice treated with CEP-37440 developed brain metastasis while 20 % of the mice in the control group developed brain metastasis. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to apoptosis, interferon signaling, and cytokines.
CEP-37440 is effective against some IBC cells that express phospho-FAK1 (Tyr 397), and its antiproliferative activity is related to its ability to decrease phospho-FAK1. Our results suggest that combinational therapies could be more effective than using CEP-37440 as a single agent.
炎性乳腺癌（IBC）是一种侵袭性强的晚期乳腺癌，预后较差。我们最近发现，粘着斑激酶1（FAK1）在IBC中上调并磷酸化（激活）。在本研究中，我们使用人IBC细胞系和IBC临床前模型研究了FAK1和间变性淋巴瘤激酶（ALK）的双重抑制剂CEP - 37440的作用。
使用IBC和三阴性乳腺癌非IBC细胞系，在几种浓度的CEP - 37440存在下进行细胞增殖测定。在体外，我们研究了总FAK1、磷酸化FAK1（Tyr 397）、总ALK和磷酸化ALK（Tyr 1604）的表达。在体内，我们使用FC - IBC02、SUM149和SUM190 IBC异种移植小鼠模型测试了CEP - 37440。
低浓度的CEP - 37440可降低IBC细胞系FC - IBC02、SUM190和KPL4的增殖，而不影响正常乳腺上皮细胞的增殖。在较高浓度下，CEP - 37440也能够抑制IBC细胞系MDA - IBC03以及三阴性非IBC细胞系MDA - MB - 231和MDA - MB - 468的增殖；IBC细胞系SUM149对该药物有轻微反应。CEP - 37440通过阻断FAK1（Tyr 397）的自磷酸化激酶活性来降低FC - IBC02、SUM190和KPL4的细胞增殖。所评估的细胞均未表达ALK。在体内，经过7周的CEP - 37440治疗后，与对照组相比，接受55mg/kg bid CEP - 37440治疗的小鼠中，SUM190、FC - IBC02和SUM149乳腺肿瘤异种移植物更小；肿瘤生长抑制（TGI）分别为79.7%、33%和23%。接受CEP - 37440治疗的FC - IBC02乳腺异种移植小鼠均未发生脑转移，而对照组中有20%的小鼠发生了脑转移。FC - IBC02细胞中的表达阵列分析表明，CEP - 37440影响与凋亡、干扰素信号传导和细胞因子相关的基因表达。
CEP - 37440对一些表达磷酸化FAK1（Tyr 397）的IBC细胞有效，其抗增殖活性与其降低磷酸化FAK1的能力有关。我们的结果表明，联合治疗可能比单独使用CEP - 37440更有效。
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