title: Inhibition of the MDM2 E3 Ligase induces apoptosis and autophagy in wild-type and mutant p53 models of multiple myeloma, and acts synergistically with ABT-737.
abstract: Intracellular proteolytic pathways have been validated as rational targets in multiple myeloma with the approval of two proteasome inhibitors in this disease, and with the finding that immunomodulatory agents work through an E3 ubiquitin ligase containing Cereblon. Another E3 ligase that could be a rational target is the murine double minute (MDM) 2 protein, which plays a role in p53 turnover. A novel inhibitor of this complex, MI-63, was found to induce apoptosis in p53 wild-type myeloma models in association with activation of a p53-mediated cell death program. MI-63 overcame adhesion-mediated drug resistance, showed anti-tumor activity in vivo, enhanced the activity of bortezomib and lenalidomide, and also overcame lenalidomide resistance. In mutant p53 models, inhibition of MDM2 with MI-63 also activated apoptosis, albeit at higher concentrations, and this was associated with activation of autophagy. When MI-63 was combined with the BH3 mimetic ABT-737, enhanced activity was seen in both wild-type and mutant p53 models. Finally, this regimen showed efficacy against primary plasma cells from patients with newly diagnosed and relapsed/refractory myeloma. These findings support the translation of novel MDM2 inhibitors both alone, and in combination with other novel agents, to the clinic for patients with multiple myeloma.
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Gu
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Chad C
authors.initials: CC
authors.lastname: Bjorklund
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D007211:Indoles / Q000494:pharmacology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D007211:Indoles; C543589:MI-63 compound; D009596:Nitrophenols; D010879:Piperazines; D013141:Spiro Compounds; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2