Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels
Bressanin, Daniela; Evangelisti, Camilla; Ricci, Francesca; Tabellini, Giovanna; Chiarini, Francesca; Tazzari, Pier Luigi; Melchionda, Fraia; Buontempo, Francesca; Pagliaro, Pasqualepaolo; Pession, Andrea; McCubrey, James A.; Martelli, Alberto M.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant hematological disorder arising in the thymus from T-cell progenitors. T-ALL mainly affects children and young adults, and remains fatal in 20% of adolescents and 50% of adults, despite progress in polychemotherapy protocols. Therefore, innovative targeted therapies are desperately needed for patients with a dismal prognosis. Aberrant activation of PI3K/Akt/mTOR signaling is a common event in T-ALL patients and portends a poor prognosis. Preclinical studies have highlighted that modulators of PI3K/Akt/mTOR signaling could have a therapeutic relevance in T-ALL. However, the best strategy for inhibiting this highly complex signal transduction pathway is still unclear, as the pharmaceutical companies have disclosed an impressive array of small molecules targeting this signaling network at different levels. Here, we demonstrate that a dual PI3K/PDK1 inhibitor, NVP-BAG956, displayed the most powerful cytotoxic effects against T-ALL cell lines and primary patients samples, when compared with a pan class I PI3K inhibitor (GDC-0941), an allosteric Akt inhibitor (MK-2206), an mTORC1 allosteric inhibitor (RAD-001), or an ATP-competitive mTORC1/mTORC2 inhibitor (KU-63794). Moreover, we also document that combinations of some of the aforementioned drugs strongly synergized against T-ALL cells at concentrations well below their respective IC50. This observation indicates that vertical inhibition at different levels of the PI3K/Akt/mTOR network could be considered as a future innovative strategy for treating T-ALL patients.
Bressanin, Daniela, & Evangelisti, Camilla, & Ricci, Francesca, & Tabellini, Giovanna, & Chiarini, Francesca, & Tazzari, Pier Luigi, & Melchionda, Fraia, & Buontempo, Francesca, & Pagliaro, Pasqualepaolo, & Pession, Andrea, & McCubrey, James A., & Martelli, Alberto M.. (August 2012). Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels. Oncotarget, 3(8), 811- 823. Retrieved from http://hdl.handle.net/10342/5689
Bressanin, Daniela, and Evangelisti, Camilla, and Ricci, Francesca, and Tabellini, Giovanna, and Chiarini, Francesca, and Tazzari, Pier Luigi, and Melchionda, Fraia, and Buontempo, Francesca, and Pagliaro, Pasqualepaolo, and Pession, Andrea, and McCubrey, James A., and Martelli, Alberto M.. "Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels". Oncotarget. 3:8. (811-823), August 2012. December 17, 2018. http://hdl.handle.net/10342/5689.
Bressanin, Daniela and Evangelisti, Camilla and Ricci, Francesca and Tabellini, Giovanna and Chiarini, Francesca and Tazzari, Pier Luigi and Melchionda, Fraia and Buontempo, Francesca and Pagliaro, Pasqualepaolo and Pession, Andrea and McCubrey, James A. and Martelli, Alberto M., "Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels," Oncotarget 3, no. 8 (August 2012), http://hdl.handle.net/10342/5689 (accessed December 17, 2018).
Bressanin, Daniela, Evangelisti, Camilla, Ricci, Francesca, Tabellini, Giovanna, Chiarini, Francesca, Tazzari, Pier Luigi, Melchionda, Fraia, Buontempo, Francesca, Pagliaro, Pasqualepaolo, Pession, Andrea, McCubrey, James A., Martelli, Alberto M.. Harnessing the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia: Eliminating activity by targeting at different levels. Oncotarget. August 2012; 3(8): 811-823. http://hdl.handle.net/10342/5689. Accessed December 17, 2018.