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

Blood. 2011 Jan 27;117(4):1270-9. doi: 10.1182/blood-2010-04-278853. Epub 2010 Nov 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Benzoquinones / pharmacology*
  • Benzoquinones / therapeutic use
  • Boronic Acids / therapeutic use*
  • Bortezomib
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Endoplasmic Reticulum Chaperone BiP
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / pharmacology*
  • Lactams, Macrocyclic / therapeutic use
  • Lymphoma, Mantle-Cell / drug therapy*
  • Lymphoma, Mantle-Cell / genetics
  • Male
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • Middle Aged
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Pyrazines / therapeutic use*
  • Receptors, Estrogen / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Benzoquinones
  • Boronic Acids
  • Endoplasmic Reticulum Chaperone BiP
  • HSP90 Heat-Shock Proteins
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Lactams, Macrocyclic
  • Molecular Chaperones
  • Pyrazines
  • Receptors, Estrogen
  • tanespimycin
  • Bortezomib