The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78.
Despite the promising introduction of the proteasome inhibitor bortezomib in the treatment of mantle cell lymphoma (MCL), not all patients respond, and resistance often appears after initial treatment. By analyzing a set of 18 MCL samples, including cell lines with constitutive or induced resistance to bortezomib, we found a high correlation between loss of sensitivity to the proteasome inhibitor and up-regulation of the prosurvival chaperone BiP/Grp78. BiP/Grp78 stabilization was ensured at a posttranscriptional level by an increase in the chaperoning activity of heat shock protein of 90 kDa (Hsp90). In bortezomib-resistant cells, both BiP/Grp78 knockdown and cell pretreatment with the Hsp90 inhibitor of the ansamycin class, IPI-504, led to synergistic induction of apoptotic cell death when combined with bortezomib. Cell exposure to the IPI-504-bortezomib combination provoked the dissociation of Hsp90/BiP complexes, leading to BiP/Grp78 depletion, inhibition of unfolded protein response, and promotion of NOXA-mediated mitochondrial depolarization. The IPI-504-bortezomib combination also prevented BiP/Grp78 accumulation, thereby promoting apoptosis and inhibiting the growth of bortezomib-resistant tumors in a mouse model of MCL xenotransplantation. These results suggest that targeting unfolded protein response activation by the inhibition of Hsp90 may be an attractive model for the design of a new bortezomib-based combination therapy for MCL.
Hematopathology Unit, Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
Gaël
G
Roué
Patricia
P
Pérez-Galán
Ana
A
Mozos
Mónica
M
López-Guerra
Sílvia
S
Xargay-Torrent
Laia
L
Rosich
Ifigènia
I
Saborit-Villarroya
Emmanuel
E
Normant
Elias
E
Campo
Dolors
D
Colomer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016227:Benzoquinones; D001897:Boronic Acids; D000091342:Endoplasmic Reticulum Chaperone BiP; D018841:HSP90 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011719:Pyrazines; D011960:Receptors, Estrogen; C112765:tanespimycin; D000069286:Bortezomib