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

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.

Eupalinolide J Suppresses the Growth of Triple-Negative Breast Cancer Cells via Targeting STAT3 Signaling Pathway

“…There are two pathways: the extrinsic and intrinsic pathways. In the intrinsic pathway, the Bcl-2 family proteins, such as proapoptotic proteins (Bad and Bax) and antiapoptotic proteins (Bcl-2 and Bcl-xl), play important roles in apoptosis induction (Duan et al, 2019). In response to proapoptotic signals, BH3-only and Bcl-2 family proteins will be activated, followed by an efflux of cytochrome c and activation of caspases (McArthur and Kile, 2018).…”

Rational Strategies for Combining Bcl-2 Inhibition with Targeted Drugs for Anti-Tumor Synergy

“…Apoptotic activity with this approach was confirmed with higher levels of cleaved caspase-3, cleaved caspase-7, cleaved PARP, and annexin V. Furthermore, pancreatic cancer organoids undergoing treatment with MLN 8237 alone demonstrated reduced Mcl-1 levels while treatment with navitoclax alone demonstrated increased Mcl-1 levels and to a lesser extent Bcl-xl levels. The addition of MLN 8237 to navitoclax counteracted the Mcl-1 upregulation seen with navitoclax only 58 . Therefore, the synergistic effect of this combined therapy may be attributable to AKA inhibition effects on Mcl-1.…”

“…Alisertib or MLN 8237 is an AKA inhibitor that has had little success as monotherapy and is therefore being increasingly examined in combination therapy. Alisertib has been observed to reduce Mcl-1 levels, and since Mcl-1 is a potential resistance mechanism to single agent BH3 mimetic therapy 58 , the addition of alisertib to BH3 mimetics is an attractive combinatorial therapy strategy. Pancreatic cancer cell lines, organoids, and xenografts exposed to either alisertib or navitoclax alone had variable sensitivity to each; however, the combination yielded increased growth inhibition.…”

Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers

“…This combination significantly improves responses in a range of solid cancers including NSCLC, ovarian, gastric and breast cancer [ 10 , 13 , 93 , 94 ]. As mentioned above, the Aurora Kinase A inhibitor MLN8237 that also induces mitotic arrest, enhances Venetoclax activity in MYCN -amplified neuroblastoma [ 48 ] and of Navitoclax in pancreatic adenocarcinoma [ 95 ].…”