Abstract
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.
©2017 American Association for Cancer Research.
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Animals
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Benzamides / administration & dosage
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Biphenyl Compounds / administration & dosage
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Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
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Carcinoma, Pancreatic Ductal / drug therapy*
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Deoxycytidine / administration & dosage
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Deoxycytidine / analogs & derivatives
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Disease Models, Animal
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Drug Resistance, Neoplasm / genetics
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Gemcitabine
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Gene Expression Regulation, Neoplastic / drug effects
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Hedgehog Proteins / antagonists & inhibitors
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Hedgehog Proteins / genetics
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Hepatocyte Growth Factor / antagonists & inhibitors*
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Hepatocyte Growth Factor / genetics
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Humans
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Imidazoles
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Mice
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Mice, Transgenic
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Neoplasm Metastasis
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / genetics
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Pyridines / administration & dosage
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Triazines
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Tumor Microenvironment / drug effects
Substances
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Benzamides
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Biphenyl Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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HGF protein, human
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Hedgehog Proteins
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Imidazoles
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Pyridines
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SHH protein, human
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Triazines
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sonidegib
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Deoxycytidine
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Hepatocyte Growth Factor
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MET protein, human
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Proto-Oncogene Proteins c-met
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capmatinib
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Gemcitabine