Matrix drug screen identifies synergistic drug combinations to augment smac mimetic activity in ovarian cancer

Anne M. Noonan, Amanda Cousins, David Anderson, Kristen P. Zeligs, Kristen Bunch, Lidia Hernandez, Yusuke Shibuya, Ian S. Goldlust, Rajarshi Guha, Marc Ferrer, Craig J. Thomas, Christina M. Annunziata

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

Original languageEnglish
Article number3784
Pages (from-to)1-19
Number of pages19
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - 2020 Dec
Externally publishedYes

Keywords

  • Birinapant
  • Docetaxel
  • Microtubule stability
  • NF-kB
  • Ovarian cancer
  • SMAC mimetics
  • Synergy
  • TNF-α

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Matrix drug screen identifies synergistic drug combinations to augment smac mimetic activity in ovarian cancer'. Together they form a unique fingerprint.

Cite this