Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma
Menée in vitro et in vivo, cette étude suggère l'intérêt de combiner le crizonitib et la gemcitabine pour le traitement d'un adénocarcinome canalaire du pancréas
Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here we developed four orthotopic mouse models employing primary human PDAC cells genetically engineered to express Firefly- and Gaussia-luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models we conducted detailed histopathological and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs and lymph nodes. Genetic characteristics were compared to the originator tumor and primary tumor cells using array-based comparative genomic hybridization, employing frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models, we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathological and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment.