Gupta, Mamta; Hendrickson, Andrea E Wahner; Yun, Seong Seok; Han, Jing Jing; Schneider, Paula A; Koh, Brian D; Stenson, Mary J; Wellik, Linda E; Shing, Jennifer C; Peterson, Kevin L; Flatten, Karen S; Hess, Allan D; Smith, B Douglas; Karp, Judith E; Barr, Sharon; Witzig, Thomas E; Kaufmann, Scott H
The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.
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Text Mining Data
Akt → mTORC1/mTORC2: " Dual mTORC1/mTORC2
inhibition diminishes Akt
activation and induces Puma dependent apoptosis in lymphoid malignancies "
Akt → mTORC1/mTORC2: " Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma dependent apoptosis in lymphoid malignancies "
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