title: Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1.
abstract: BACKGROUND
  Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The 'unfolded protein response' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib.
  
  
  METHODS
  Expression of XBP-1 and other regulators of the unfolded protein response were measured in myeloma and other cancer cell lines and two cohorts of patients with refractory myeloma and correlated with sensitivity/response to bortezomib. Bortezomib-resistant myeloma cell lines were derived and the effects on expression of unfolded protein response regulators, immunoglobulin secretion, proteasome activity and cross-resistance to cytotoxic drugs and tunicamycin determined. The consequences of manipulation of XBP-1 levels for sensitivity to bortezomib were tested.
  
  
  RESULTS
  Low XBP-1 levels predicted poor response to bortezomib, both in vitro and in myeloma patients. Moreover, myeloma cell lines selected for resistance to bortezomib had down-regulated XBP-1 and immunoglobulin secretion. Expression of ATF6, another regulator of the unfolded protein response, also correlated with bortezomib sensitivity. Direct manipulation of XBP-1 levels had only modest effects on sensitivity to bortezomib, suggesting it is a surrogate marker of response to bortezomib rather than a target itself.
  
  
  CONCLUSIONS
  The unfolded protein response may be a relevant target pathway for proteasome inhibitors in the treatment of myeloma and its regulator XBP-1 is a potential response marker. (The BIR study was registered with Australian Clinical Trial Registry Number 12605000770662).
authors: Haematology Consulting RooLiverpool Hospital, Locked Bag 7090, Liverpool BC NSW 1871, Australia.
authors: Silvia C W
authors: SC
authors: Ling
authors: Edwin K K
authors: EK
authors: Lau
authors: Ammira
authors: A
authors: Al-Shabeeb
authors: Angela
authors: A
authors: Nikolic
authors: Albert
authors: A
authors: Catalano
authors: Harry
authors: H
authors: Iland
authors: Noemi
authors: N
authors: Horvath
authors: P Joy
authors: PJ
authors: Ho
authors: Simon
authors: S
authors: Harrison
authors: Shaun
authors: S
authors: Fleming
authors: Douglas E
authors: DE
authors: Joshua
authors: John D
authors: JD
authors: Allen
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D000071717:X-Box Binding Protein 1
chemical_list: D051702:Activating Transcription Factor 6; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D000069286:Bortezomib