Novel Synergistic Combination of Mitotic Arrest and Promotion of Apoptosis for Treatment of Pancreatic Adenocarcinoma

Zhijian Duan, Danielle Chinn, Mei Juan Tu, Qian Yu Zhang, Jasmine Huynh, Justin Chen, Philip Mack, Aiming Yu, Edward Kim

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The BCL-2 family of proteins, including anti-apoptotic members BCL-2, BCL-XL and MCL-1, are part of a complex network that controls apoptosis. BH3-mimetics such as ABT-263 inhibit anti-apoptotic BCL-2 proteins and have been developed as potential cancer therapeutics. Aurora Kinase A (AKA) is over-expressed in pancreatic cancer (PC) and controls G2-M transition during mitosis and AKA inhibitors have been developed that induce mitotic arrest. We hypothesized that mitotic arrest induced by AKA inhibition may sensitize PC to accelerated apoptosis by a BH3-mimetic. Our results demonstrated that ABT-263 plus MLN8237 treatment showed greater activity than either single drug alone, as well as strong synergism, in the inhibition of growth of pancreatic cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) and PC patient-derived organoids (PDOs). The higher efficacy of combination treatment was attributable to the higher levels of induction of apoptosis and reduction of MCL-1 in PC cells and PDOs. In addition, combination therapy was more effective than single drug in the suppression of tumor growth in AsPC-1 xenograft mouse models. Together, our findings suggest that combination therapy with ABT-263 and MLN8237 should be considered for further exploration as a novel treatment of deadly PC disease.

Original languageEnglish (US)
Pages (from-to)683-692
Number of pages10
JournalTranslational Oncology
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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