Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma.
Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1158/1535-7163.mct-16-0834
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发表时间：
2017-11
影响因子：
5.7
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Aguilera KY;Huang H;Du W;Hagopian MM;Wang Z;Hinz S;Hwang TH;Wang H;Fleming JB;Castrillon DH;Ren X;Ding K;Brekken RA
细胞外基质（ECM）是胰腺导管腺癌（PDA）的主要成分，富含纤维状胶原，促进肿瘤细胞存活和化疗耐药。盘状蛋白结构域受体1 （DDR1）是一种酪氨酸激酶受体，可特异性结合原纤维胶原，并参与促进细胞增殖、迁移、粘附、ECM重塑和对生长因子的反应。我们发现胶原诱导的DDR1激活通过蛋白酪氨酸激酶2 （PYK2）和假足富集的非典型激酶1 （PEAK1）在胰腺癌细胞中刺激致瘤前信号传导。用ATP竞争性口服小分子激酶抑制剂（7rh）对DDR1进行药理学抑制，可消除胰腺肿瘤细胞中胶原诱导的DDR1信号，从而减少集落的形成和迁移。此外，7rh对DDR1的抑制在原位异种移植物和原位胰腺肿瘤的化疗中显示出惊人的疗效，可以显著降低DDR1的激活和下游信号，减轻原发肿瘤负担，改善化学反应。这些数据表明，靶向胶原信号结合传统的细胞毒性化疗有可能改善胰腺癌患者的预后。
The extracellular matrix (ECM), a principal component of pancreatic ductal adenocarcinoma (PDA), is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors. We found that collagen-induced activation of DDR1 stimulated pro-tumorigenic signaling through protein tyrosine kinase 2 (PYK2) and pseudopodium-enriched atypical kinase 1 (PEAK1) in pancreatic cancer cells. Pharmacologic inhibition of DDR1 with an ATP competitive orally available small molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and consequently reduced colony formation and migration. Furthermore, the inhibition of DDR1 with 7rh showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors where it significantly reduced DDR1 activation and downstream signaling, reduced primary tumor burden, and improved chemoresponse. These data demonstrate that targeting collagen-signaling in conjunction with conventional cytotoxic chemotherapy has the potential to improve outcome for pancreatic cancer patients.