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

Novel Synergistic Combination of Mitotic Arrest and Promotion of Apoptosis for Treatment of Pancreatic Adenocarcinoma. Transl Oncol. 2019 Mar 04;12(4):683-692 Authors: Duan Z, Chinn D, Tu MJ, Zhang QY, Huynh J, Chen J, Mack P, Yu AM, Kim EJ 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 an...
Source: Translational Oncology - Category: Cancer & Oncology Authors: Tags: Transl Oncol Source Type: research