title: HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma.
abstract: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma (MCL). Intrinsic resistance can occur through activation of the nonclassical NF-κB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer heat shock protein 90 (HSP90) inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IκB kinase α in MCL lines and CD40-dependent B cells, with downstream loss of MAPK and nonclassical NF-κB signaling. A proteome-wide analysis in MCL lines and an MCL patient-derived xenograft identified a restricted set of targets from HSP90 inhibition that were enriched for factors involved in B-cell receptor and JAK/STAT signaling, the nonclassical NF-κB pathway, cell-cycle regulation, and DNA repair. Finally, multiple HSP90 inhibitors potently killed MCL lines in vitro, and the clinical agent AUY922 was active in vivo against both patient-derived and cell-line xenografts. Together, these findings define the HSP90-dependent proteome in MCL. Considering the disappointing clinical activity of HSP90 inhibitors in other contexts, trials in patients with MCL will be essential for defining the efficacy of and mechanisms of resistance after ibrutinib failure.
authors.affiliation: Department of Medical Oncology and.
authors.forename: Caron
authors.initials: C
authors.lastname: Jacobson
authors.affiliation: Department of Medical Oncology and.
authors.forename: Nadja
authors.initials: N
authors.lastname: Kopp
authors.affiliation: Department of Medical Oncology and.
authors.forename: Jacob V
authors.initials: JV
authors.lastname: Layer
authors.affiliation: Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Redd
authors.affiliation: Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research, Ludwig-Maximilians University, Munich, Germany.|German Cancer Consortium, Heidelberg, Germany.|German Cancer Research Center, Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Tschuri
authors.affiliation: Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research, Ludwig-Maximilians University, Munich, Germany.|German Cancer Consortium, Heidelberg, Germany.|German Cancer Research Center, Heidelberg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Haebe
authors.affiliation: Department of Medical Oncology and.
authors.forename: Diederik
authors.initials: D
authors.lastname: van Bodegom
authors.affiliation: Department of Medical Oncology and.
authors.forename: Liat
authors.initials: L
authors.lastname: Bird
authors.affiliation: Department of Medical Oncology and.|Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Department of Medical Oncology and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Christodoulou
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Amy
authors.initials: A
authors.lastname: Saur
authors.affiliation: Department of Medical Oncology and.
authors.forename: Trevor
authors.initials: T
authors.lastname: Tivey
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health, Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zapf
authors.affiliation: Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research, Ludwig-Maximilians University, Munich, Germany.|German Cancer Consortium, Heidelberg, Germany.|German Cancer Research Center, Heidelberg, Germany.
authors.forename: Deepak
authors.initials: D
authors.lastname: Bararia
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health, Munich, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA; and.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research, Ludwig-Maximilians University, Munich, Germany.|German Cancer Consortium, Heidelberg, Germany.|German Cancer Research Center, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Weigert
authors.affiliation: Department of Medical Oncology and.|Broad Institute, Harvard University and Massachusetts Institute of Technology, Cambridge, MA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020125:Mutation, Missense; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D012118:Resorcinols; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine