An attractive therapeutic target, mTOR pathway, in ALK+ anaplastic large cell lymphoma

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and a key regulator of cell growth and proliferation. Persistent activation of the mTOR pathway is a common event in several human tumors. Rapamycin, a macrolide antibiotic, inhibits the mTOR pathway and derivatives of rapamycin are currently being investigated as promising therapeutic agents in several cancers. Recent in vitro studies, including the report by Marzec et al discussed in this commentary, have reported activation of the mTOR pathway in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL). ALK+ ALCL is a distinctive type of T/null-cell non-Hodgkin lymphoma characterized by the presence of chromosomal translocations involving the ALK gene, the most frequent being the t(2;5)(p23;q35). Marzec et al and others have shown that inhibition of mTOR pathway induces cell cycle arrest and apoptosis in ALK+ ALCL, thereby establishing rapamycin or, more likely, its derivatives as potential effective therapeutic agents. In addition, Marzec et al provide new insights by demonstrating that nucleophosmin-ALK induces activation of the mTOR pathway via the mitogen-induced extracellular kinase/extracellular signal-regulated kinase signaling pathway, in addition to the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Furthermore, a combination of an mTOR inhibitor with an inhibitor of the upstream mitogen-induced extracellular kinase/extracellular signal-regulated kinase pathway was more effective at inhibiting ALK+ ALCL cell proliferation than either inhibitor alone. In conclusion, there is growing evidence that the mTOR pathway is activated in ALK+ ALCL and that this pathway can be targeted as part of combination chemotherapy in patients with these lymphomas.