Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemotherapy- and radiotherapy-resistant tumors. The c-Met and Hedgehog (Hh) pathways have been shown previously by our group to be key regulatory pathways in the primary tumor growth and metastases formation. Targeting both the HGF/c-Met and Hh pathways has shown promising results in preclinical studies; however, the benefits were not readily translated into clinical trials with PDAC patients. In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in combination with the chemotherapy treatment. Mol Cancer Ther; 16(11); 2399–409. ©2017 AACR .

中文翻译：

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刺猬和c-Met途径对胰腺癌治疗的双重抑制

胰腺导管腺癌（PDAC）是对化疗和放疗耐药性最高的肿瘤之一。我们小组先前已证明c-Met和Hedgehog（Hh）途径是原发性肿瘤生长和转移形成中的关键调控途径。在临床前研究中，针对HGF / c-Met和Hh途径均显示出可喜的结果。然而，这种益处并未轻易转化为PDAC患者的临床试验。在这项研究中，利用PDAC的小鼠模型，我们发现抑制HGF / c-Met或Hh途径可使PDAC肿瘤对吉西他滨敏感，从而导致原发肿瘤体积减少以及转移性肿瘤负荷的显着降低。但是，长期治疗单一HGF / c-Met或Hh抑制剂会导致对这些单一抑制剂的耐药性，可能是因为单次c-Met处理导致Shh表达增强，反之亦然。同时靶向HGF / c-Met和Hh途径克服了对单一抑制剂治疗的耐药性，与化学疗法结合使用可产生更强的抗肿瘤作用。分子癌疗法；16（11）; 2399–409。©2017 AACR。