Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma

摘要: ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin whose treatment benefited from crizotinib development, dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/mTOR, indispensable for survival ALK-driven tumors.Despite the positive impact targeted in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include design second generation drugs and use combined therapies that simultaneously target multiple nodes essential cells survival. We investigated effects ALK/mTOR inhibition. observed specific synergistic effect combining ALK inhibitors with an mTOR inhibitor (temsirolimus), ALK+ lymphoma cells. The cooperation resulted increased inhibition effectors, compared single treatments, block G0/G1 phase induction apoptosis. combination was able prevent selection clones, while long-term exposure agents led establishment cell lines, either or temsirolimus. In vivo, mice injected Karpas 299 treated low dose showed complete regression tumors, only partial obtained agents-treated mice. Upon stop significantly delay tumor relapses. Re-challenge relapsed tumors at higher full xenografts group, but not lorlatinib alone. conclusion, our data suggest could be valuable therapeutic option ALCL patients.