Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2.
The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapamycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. Furthermore, knockdown of the mTORC2 component rictor, but not the mTORC1 component raptor, inhibited rapamycin-induced Akt phosphorylation in lymphoma cells. Addition of the histone deacetylase inhibitor (HDI) LBH589 (LBH) overcame rapamycin resistance by blocking mTOR, thus preventing Akt activation. Further studies support the involvement of the protein phosphatase PP1 in LBH-mediated Akt dephosphorylation, which could be mimicked by knockdown of HDAC3. This is the first demonstration that a HDI such as LBH can overcome rapamycin resistance through a phosphatase that antagonizes mTORC2 activation. These results provide a mechanistic rationale for a clinical trial of a combination of HDI and mTOR inhibitors for DLBCL.
Gupta
Mamta
M
Division of Hematology and Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Ansell
Stephen M
SM
Novak
Anne J
AJ
Kumar
Shaji
S
Kaufmann
Scott H
SH
Witzig
Thomas E
TE
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007211:Indoles; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D000077767:Panobinostat; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; C493245:CRTC2 protein, human; D039561:Eukaryotic Initiation Factor-4E; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000077767:Panobinostat; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D006655:Histone Deacetylases; D020123:Sirolimus