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：

---

Hedgehog 和 c-Met 通路的双重抑制用于胰腺癌治疗

胰腺导管腺癌 (PDAC) 是最耐化疗和放疗的肿瘤之一。我们小组之前已经证明 c-Met 和 Hedgehog (Hh) 通路是原发性肿瘤生长和转移形成的关键调控通路。针对 HGF/c-Met 和 Hh 通路在临床前研究中显示出有希望的结果；然而，这些益处并不容易转化为 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 通路可使 PDAC 肿瘤对吉西他滨敏感，从而减少原发肿瘤体积并显着减少转移性肿瘤负荷。然而，单一 HGF/c-Met 或 Hh 抑制剂的长期治疗会导致对这些单一抑制剂的耐药性，可能是因为单一的 c-Met 处理导致 Shh 的表达增强，反之亦然。同时靶向 HGF/c-Met 和 Hh 通路克服了对单一抑制剂治疗的耐药性，并与化疗治疗相结合产生了更有效的抗肿瘤作用。摩尔癌症治疗; 16(11); 2399-409。©2017 AACR。