title: Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma.
abstract: Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide-sensitive H929 MM cell lines, were also observed in PomDex-treated lenalidomide-resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide-sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex-treated samples, highlighted by the modulation of pro-apoptotic pathways in lenalidomide-resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide-resistant setting.
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Rychak
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Mendy
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Shi
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Leisten
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Miller
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Narla
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Heather K
authors.initials: HK
authors.lastname: Raymon
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Chad C
authors.initials: CC
authors.lastname: Bjorklund
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Anjan
authors.initials: A
authors.lastname: Thakurta
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Gandhi
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cathers
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Daniel
authors.affiliation: Celgene Corporation, San Diego, CA, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Lopez-Girona
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D000077269:Lenalidomide; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide; D000077269:Lenalidomide
keywords: anti-proliferative; apoptosis; dexamethasone; myeloma; pomalidomide; resistance