对付EMT耐药的AXL抑制剂相关信息

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First Axl inhibitor enters clinical trials

First Axl inhibitor enters clinical trials.pdf (555.57 KB, 下载次数: 65)

costa_na · 发表于 2013-12-17 17:34:08

MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to to EGFR kinase inhibitors due to MET or AXL activation

In non-small cell lung cancer (NSCLC) with EGFR mutations, acquired resistance to EGFR kinase inhibitors (EGFR-TKIs) can occur through generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1-rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs due to MET or AXL activation or ROS1 rearrangement.

NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants

The MET proto-oncogene product, which is the receptor for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and metastatic progression. Point mutations in MET lead to the aberrant activation of the receptor in many types of human malignancies, and the deregulated activity of MET has been correlated with tumor growth, invasion, and metastasis. MET has therefore attracted considerable attention as a potential target in anticancer therapy. Here, we report that a novel MET kinase inhibitor, NPS-1034, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. NPS-1034 inhibited the proliferation of cells expressing activated MET and promoted the regression of tumors formed from such cells in a mouse xenograft model through anti-angiogenic and pro-apoptotic actions. NPS-1034 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Furthermore, when tested on 27 different MET variants, NPS-1034 inhibited 15 of the 17 MET variants that exhibited autophosphorylation with nanomolar potency; only the F1218I and M1149T variants were not inhibited by NPS-1034. Notably, NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that NPS-1034 can be used as a potent therapeutic agent for human malignancies bearing MET point mutations or expressing activated MET.

二师兄 · 发表于 2014-7-27 10:18:21

Science子刊揭示癌症耐药根源

来自麻省理工学院的一项新研究揭示，ErbB抑制剂耐药形成大部分都是因为一种叫做AXL的蛋白帮助癌细胞避开了ErbB抑制剂的效应，使得它们无限生长所致。麻省理工学院生物工程学系主任Doug Lauffenburger教授说，这些研究结果表明，组合靶向AXL和ErbB受体的药物，有可能是一种更好的抗肿瘤方法。

生物通报道尽管抗癌药物ErbB抑制剂已在许多的肺癌、乳腺癌、结肠癌和其他类型癌症患者的治疗中取得了极大的成功，但也有许多其他的患者对ErbB药物无反应，甚至在那些对ErbB抑制剂有反应的患者中，肿瘤通常也可能再度复发。生物通 www.ebiotrade.com
来自麻省理工学院的一项新研究揭示，这种耐药形成大部分都是因为一种叫做AXL的蛋白帮助癌细胞避开了ErbB抑制剂的效应，使得它们无限生长所致。麻省理工学院生物工程学系主任Doug Lauffenburger教授说，这些研究结果表明，组合靶向AXL和ErbB受体的药物，有可能是一种更好的抗肿瘤方法。这项研究发表在8月6日的《科学信号》（Science Signaling）杂志上。
“耐药是当前癌症的主要挑战。尽管人们提出了许多针对特定基因的靶向治疗，确定了对它们起作用的药物，但耐药这一问题却常常存在，”Lauffenburger说。生物通 www.ebiotrade.com
表皮生长因子受体（EGFRs）家族ErbBs，常常在癌细胞中过度活化，导致它们失控性生长和分裂。药物吉非替尼（Iressa）被用于治疗肿瘤过表达一种ErbB突变体的肺癌患者，赫赛汀（Herceptin）靶向的则是存在于某些乳癌类型中的另一个ErbB家族成员。
“有许多极好的药物靶向EGFR自身或是这一家族的其他成员，但它们都具有这些局限，”Lauffenburger说。生物通 www.ebiotrade.com
系统分析
在新研究中，Lauffenburger和同事们着手鉴别了帮助肿瘤细胞对EGFR抑制剂或其他ErbB抑制剂耐药的因子。为此，他们开发了一种新的计算机模型，将它应用于癌细胞系百科全书（Cancer Cell Line Encyclopedia），这一大数据集涵盖了大约1000种人类癌症细胞系和它们对于不同药物反应的信息。生物通 www.ebiotrade.com
在论文的主要作者、生物工程学研究生Aaron Meyer的领导下，研究人员开发出了一种机器学习程序，它可以筛选数据并搜索导致肿瘤细胞对EGFR抑制剂耐药的数对过表达蛋白。在这种情况下，他们搜查了数据库中每个可能与EGFR蛋白组合的蛋白质，一次一对。
通过这一分析，研究人员发现EGFR与AXL受体配对，似乎是EGFR抑制剂耐药最强有力的标记物。他们发现这种模式存在于肺癌、乳腺癌和胰腺癌等许多的癌症类型中。生物通 www.ebiotrade.com
以往的一些研究证实，在一种特殊肿瘤中过表达AXL与EGFR抑制剂耐药有关，但这是第一次系统研究证实这一相关性。这一“系统生物学”方法，将焦点放在生物学系统的复杂相互作用上，对于发现能够协同作用破坏癌症防御机制的新药至关重要。
Lauffenburger说：“众所周知，当你着眼于一个单一的信号通路时，你无法得到一种有效的治疗。最终你将获得耐药。你得看看组合信号通路，你要看到整个的互作网络。这是唯一的方法。”生物通 www.ebiotrade.com
与秘密有关的一些线索
随后，在实验室培育癌细胞实验中，研究人员发现AXL蛋白往往和EGFR一起聚集在细胞表面，因此当EGFR激活时，AXL也活化。AXL随后不仅进一步刺激了EGFR靶向的相同细胞机器，还有其他引起细胞生长和分裂的信号通路。AXL还帮助使细胞变得更加具有活力，使得癌症扩散至全身。生物通 www.ebiotrade.com
研究人员还证实，除了EGFR，其他的ErbB家族成员同样地与AXL聚集在一起。这表明，AXL抑制或许还能有效地治疗依赖于ErbB2的乳腺癌或是过表达ErbB3的卵巢癌。
加州大学旧金山分校医学助理教授Trever Bivona（未参与该研究）说，这项研究阐明了EGFR抑制剂初步治疗后推动肿瘤复发的，EGFR和其他蛋白之间的复杂相互作用，有可能帮助研究人员开发改进治疗。生物通 www.ebiotrade.com
“这些研究发现表明，受体激酶相互作用破坏治疗敏感性的方式非常的复杂，”Bivona说。
以往在三阴乳腺癌细胞中发现有高水平的AXL，这些癌细胞缺乏最常见的3种乳腺癌标记物：雌激素受体、孕激素受体和HER2受体。Lauffenburger说，新研究发现或许可以解释EGFR抑制剂无法对这些肿瘤起作用的原因，尽管它们具有高水平的EGFR。生物通 www.ebiotrade.com
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“我们尤其对三阴乳腺癌细胞感兴趣，关于它们为何不会对EGFR抑制剂产生反应，一直是一个谜题，”他说。生物通 www.ebiotrade.com
新研究表明单独使用AXL抑制剂，或是组合EGFR抑制剂，有可能是一种有效的三阴乳腺癌治疗方法，现在所采用的几种化疗药物治疗这一疾病都具有严重的副作用。当前一些临床试验正在测试AXL抑制剂对不同种类癌症的效应，Lauffenburger现正计划在小鼠中开展研究，调查组合AXL和EGFR信号通路抑制剂的效应。

二师兄 · 发表于 2014-7-27 10:20:55

1.pdf (753.13 KB, 下载次数: 45)

Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer.pdf (4.19 MB, 下载次数: 41)

Axl基因在肿瘤进展中的作用.pdf (868.14 KB, 下载次数: 48)

Differential expression of CRKL and AXL genes in lung adenocarcinoma subtypes ac.pdf (1.47 MB, 下载次数: 40)

First Axl inhibitor enters clinical trials.pdf (555.57 KB, 下载次数: 47)

Gas6 Axl mediates tumor cell apoptosis,migration and invasion and predicts the c.pdf (2.26 MB, 下载次数: 47)

Gas6 induces cancer cell migration and epithelial–mesenchymal transition throug.pdf (1.12 MB, 下载次数: 51)

gunslinger · 发表于 2014-9-9 20:20:50

有药的新消息吗？

lv1170 · 发表于 2014-9-9 20:28:33

希望能尽快上市！

costa_na · 发表于 2014-9-11 18:36:18

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non–small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.

ng.2330.pdf (1.53 MB, 下载次数: 43)

costa_na · 发表于 2014-9-11 19:04:57

Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis

Dysregulation of Axl and its ligand growth arrest-specific 6 is implicated in the pathogenesis of several human cancers. In this study, we have used RNAi and monoclonal antibodies to assess further the oncogenic potential of Axl. Here we show that Axl knockdown reduces growth of lung
and breast cancer xenograft tumors. Inhibition of Axl expression attenuates breast cancer cell migration and inhibits metastasis to the lung in an orthotopic model, providing the first in vivo evidence that links Axl directly to cancer metastasis. Axl knockdown in endothelial cells impaired tube formation and this effect was additive with anti-vascular endothelial growth factor (VEGF). Further analysis demonstrated that Axl regulates endothelial cell functions by modulation of signaling through angiopoietin/Tie2 and Dickkopf (DKK3) pathways. We have developed and characterized Axl monoclonal antibodies that attenuate non-small cell lung carcinoma xenograft growth by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis. Our data demonstrate that Axl plays multiple roles in tumorigenesis and that therapeutic antibodies against Axl may block Axl functions not only in malignant tumor cells but also in the tumor stroma. The additive effect of Axl inhibition with anti-VEGF suggests that blocking Axl function could be an effective approach for enhancing antiangiogenic therapy.

onc2009212a.pdf (1.02 MB, 下载次数: 44)

costa_na · 发表于 2014-9-11 19:06:41

AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells

Despite significant progress in the treatment of breast cancer, particularly through the use of targeted therapy, relapse and chemoresistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial-to-mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them to reverse EMT and to attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL using MP470 (Amuvatinib) reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with the expression of stem cell genes, regulation of metastases genes, increased tumorigenicity and was important for BCSC invasion and migration. Inactivation of AXL also led to the downregulation of nuclear factor-kB pathway and reduced tumor formation in vivo. Taken together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anticancer therapies and to reduce breast cancer recurrence and metastases.

onc201357a.pdf (1.84 MB, 下载次数: 41)

costa_na · 发表于 2014-9-11 19:08:40

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

Axl is a receptor that induces proliferation, migration and invasion in cancer. In this study, we show that specific microRNAs (miRNAs) target the 30-UTR of Axl. Luciferase-reporter assays with wild-type and deleted miR-34 and miR-199a/b seed sequences of Axl 30-UTR confirmed the specificity of targeting. An inverse correlation between Axl protein and miR-34a expression in a panel of non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer (BRC) cell lines was observed, while miR-199a/b expression was completely suppressed. Pre-miR transfection inhibited in vitro migration and invasion and, in vivo, reduced the number of distant lung- or liver-metastases in a chorion-allantoicmembrane (CAM) assay. Moreover, methylation-specific PCR on bisulfite-converted DNA obtained from the cell lines showed that the miR-34a promoter methylation status was inversely correlated with its expression, and that miR-199a/b promoter regions were methylated in all cells tested. In a panel of NSCLC tissues (n¼44), miR-34a and miR-199a/b were found to be downregulated and significantly co-expressed. A lower expression of all three miRs was significantly associated with squamous histotypes, and, in a preliminary series, NSCLC patients with miR-34a upregulation showed a positive association towards a longer survival. These results indicate that Axl receptor expression can be regulated by miR-34a and miR-199a/b, which are suppressed by promoter methylation in solid cancer cells.

onc201113a.pdf (1.12 MB, 下载次数: 42)