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Oncotarget. 2015 Nov 10;6(35):37410-25. doi: 10.18632/oncotarget.6138.

SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells.

Author information

1
Department of Pathology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
2
Debiopharm International SA, Lausanne, Switzerland.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
4
Breast Medical Oncology Group, Yale Cancer Center, New Haven, CT, USA.
5
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
6
Departments of Dermatology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.

Abstract

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.

KEYWORDS:

SMAC mimetic; bromodomain inhibitor; combination therapy; high throughput screening; lung adenocarcinoma

PMID:
26485762
PMCID:
PMC4741938
DOI:
10.18632/oncotarget.6138
[Indexed for MEDLINE]
Free PMC Article

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