The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Mol Cancer Ther. 2017 Nov;16(11):2399-2409. doi: 10.1158/1535-7163.MCT-16-0452. Epub 2017 Sep 1.
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. .
胰腺导管腺癌 (PDAC) 是对化疗和放疗最具耐药性的肿瘤之一。我们小组之前的研究表明，c-Met 和 Hedgehog (Hh) 途径是原发性肿瘤生长和转移形成的关键调节途径。靶向 HGF/c-Met 和 Hh 途径在临床前研究中显示出了有前景的结果；然而，这些益处并没有很容易地转化为 PDAC 患者的临床试验。在这项研究中，我们利用 PDAC 的小鼠模型表明，抑制 HGF/c-Met 或 Hh 途径均可使 PDAC 肿瘤对吉西他滨敏感，从而导致原发性肿瘤体积减小，转移性肿瘤负担显著降低。然而，长期单一 HGF/c-Met 或 Hh 抑制剂治疗会导致对这些单一抑制剂的耐药性，这可能是因为单一 c-Met 治疗会导致 Shh 的表达增强，反之亦然。同时靶向 HGF/c-Met 和 Hh 途径可克服单一抑制剂治疗的耐药性，并与化疗联合治疗产生更强的抗肿瘤作用。
