mTOR inhibitor RAD001 promotes metastasis in a rat model of pancreatic neuroendocrine cancer
Menée sur des rats, cette étude montre que l'évérolimus, un inhibiteur de la voie mTOR, favorise le processus métastatique d'un cancer du pancréas
Inhibition of mTOR (mammalian target of rapamycin) is commonly considered a valid target in cancer treatment, but this assertion does not address effects on the immune microenvironment that may be detrimental to cancer treatment. Here we show how administration of the mTOR inhibitor RAD001 (everlimus) results in occurrence of distant metastasis in a rat model of pancreatic cancer. RAD001 was adminstered twice weekly for 4.5 weeks as a single treatment or combined with [177Lu-DOTA,Tyr3]octreotate (177Lu-DOTATATE), the latter of which targets the somatostatin receptor-2. The hypothesised synergistic therapeutic effect of RAD001 combined with 177Lu-DOTATATE was however not observed in our experiments. The combination showed to be less effective than 177Lu-DOTATATE alone. Unexpectedly, tumor metastasis was observed in 77% of the subjects treated with RAD001, either alone or as part of the combination treatment. This was a striking effect because metastasis did not occur in control or 177Lu-DOTATATE-treated animals, including if the primary tumor was surgically removed. These findings may be important clinically among non-compliant patients or patients that discontinue RAD001 therapy due to adverse effects.
Cancer Research 2012