SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells.
Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c-IAP1, c-IAP2, and XIAP. Non-canonical NF-κB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143-containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here.
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Casey G
CG
Langdon
Debiopharm International SA, Lausanne, Switzerland.
Norbert
N
Wiedemann
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.|Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
Matthew A
MA
Held
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Ramanaiah
R
Mamillapalli
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Pinar
P
Iyidogan
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Nicholas
N
Theodosakis
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.|Breast Medical Oncology Group, Yale Cancer Center, New Haven, CT, USA.
James T
JT
Platt
Debiopharm International SA, Lausanne, Switzerland.
Frederic
F
Levy
Debiopharm International SA, Lausanne, Switzerland.
Gregoire
G
Vuagniaux
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Shaomeng
S
Wang
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.|Departments of Dermatology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Marcus W
MW
Bosenberg
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
David F
DF
Stern
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D001392:Azocines / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*; D013997:Time Factors; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C561695:(+)-JQ1 compound; D051017:Apoptosis Regulatory Proteins; D001381:Azepines; D001392:Azocines; D001559:Benzhydryl Compounds; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D016328:NF-kappa B; D043823:Taxoids; D059003:Topoisomerase Inhibitors; D014230:Triazoles; D000077143:Docetaxel; D000077146:Irinotecan; D017239:Paclitaxel; D002166:Camptothecin
SMAC mimetic; bromodomain inhibitor; combination therapy; high throughput screening; lung adenocarcinoma