Inhibition of mammalian target of rapamycin signaling by everolimus induces senescence in adult T-cell leukemia/lymphoma and apoptosis in peripheral T-cell lymphomas

Abstract

HTLV-I-associated adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I (HTLV-I)-negative peripheral T-cell lymphomas carry poor prognosis mainly because of acquired resistance to chemotherapy. We have shown that this disease is responsive to the combination of zidovudine and interferon-α. However, long-term maintenance therapy with this combination is associated with side effects affecting patient quality of life and hence more tolerated alternatives are needed. In this submission, we explored the effect of the mammalian target of rapamycin (mTOR) complex-1 (mTORC1) inhibitor everolimus (RAD001) on ATL and HTLV-negative malignant T-cell lines. We demonstrate that, at clinically achievable concentrations, long-term treatment with everolimus resulted in a dramatic inhibitory effect on the growth of HTLV-I-positive and -negative malignant T-cells, while normal resting or activated T-lymphocytes were resistant. Everolimus specifically induced oncoprotein Tax degradation and senescence in ATL cells and cell cycle arrest and apoptosis in HTLV-I-negative malignant T-cells. Everolimus-mediated apoptosis was also associated with an upregulation of p53 upregulated modulator of apoptosis (PUMA-α) proteins, an increase in Bax proteins and downregulation of Bcl-x(L) proteins in all tested HTLV-I-positive and -negative malignant cell lines. These results support a therapeutic role for everolimus, particularly as long-term maintenance therapy in patients with ATL and other HTLV-I-negative peripheral T-cell lymphomas.