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.

中文翻译：

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抑制盘状结构域受体 1 可降低胰腺导管腺癌中胶原介导的致瘤性

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耐药性。盘状结构域受体 1 (DDR1) 是一种受体酪氨酸激酶，可特异性结合纤维状胶原蛋白，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 激活通过胰腺癌细胞中的蛋白酪氨酸激酶 2 (PYK2) 和富含假足的非典型激酶 1 (PEAK1) 刺激了促肿瘤信号。用 ATP 竞争性口服小分子激酶抑制剂 (7rh) 对 DDR1 的药理学抑制消除了胰腺肿瘤细胞中胶原诱导的 DDR1 信号传导，从而减少了集落形成和迁移。此外，用 7rh 抑制 DDR1 与化学疗法在原位异种移植物和本土胰腺肿瘤中显示出惊人的疗效，显着减少了 DDR1 激活和下游信号传导，减少了原发性肿瘤负荷，并改善了化学反应。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疗有可能改善胰腺癌患者的预后。摩尔癌症治疗; 16(11); 2473-85。©2017 AACR。用 7rh 抑制 DDR1 与化学疗法结合在原位异种移植物和本土胰腺肿瘤中显示出惊人的疗效，它显着减少了 DDR1 激活和下游信号传导，减少了原发性肿瘤负荷，并改善了化学反应。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疗有可能改善胰腺癌患者的预后。摩尔癌症治疗; 16(11); 2473-85。©2017 AACR。用 7rh 抑制 DDR1 与化学疗法在原位异种移植物和本土胰腺肿瘤中显示出惊人的疗效，显着减少了 DDR1 激活和下游信号传导，减少了原发性肿瘤负荷，并改善了化学反应。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疗有可能改善胰腺癌患者的预后。摩尔癌症治疗; 16(11); 2473-85。©2017 AACR。这些数据表明，靶向胶原信号与常规细胞毒性化疗相结合有可能改善胰腺癌患者的预后。摩尔癌症治疗; 16(11); 2473-85。©2017 AACR。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疗有可能改善胰腺癌患者的预后。摩尔癌症治疗; 16(11); 2473-85。©2017 AACR。