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 protumorigenic 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. Mol Cancer Ther; 16(11); 2473–85. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2327][1] [1]: /lookup/volpage/16/2327?iss=11

中文翻译：

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Discoidin域受体1的抑制作用降低胰腺导管腺癌中的胶原介导的致瘤性。

细胞外基质（ECM）是胰腺导管腺癌（PDA）的主要成分，富含纤维状胶原蛋白，可促进肿瘤细胞存活和化学抗药性。Discoidin域受体1（DDR1）是一种受体酪氨酸激酶，可以特异性结合原纤维胶原蛋白，并且与促进细胞增殖，迁移，粘附，ECM重塑以及对生长因子的反应有关。我们发现胶原蛋白诱导的DDR1激活通过蛋白质酪氨酸激酶2（PYK2）和富含伪足蛋白的非典型激酶1（PEAK1）刺激了胰腺癌细胞的致瘤信号。DDR竞争性口服小分子激酶抑制剂（7rh）对DDR1的药理抑制作用消除了胰腺肿瘤细胞中胶原蛋白诱导的DDR1信号转导，从而减少了菌落的形成和迁移。此外，在原位异种移植和原发性胰腺肿瘤中，结合7rh抑制DDR1表现出惊人的疗效，可显着降低DDR1激活和下游信号传导，减轻原发性肿瘤负担并改善化学反应。这些数据表明，靶向胶原蛋白信号传导结合常规细胞毒性化学疗法具有改善胰腺癌患者预后的潜力。分子癌疗法；16（11）; 2473–85。©2017 AACR。本文在本期要点[p。2327] [1] [1]：