Background: Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States. Approximately 20% of human CRCs possess mutations in the PIK3CA gene, resulting in a constitutively active form of phosphoinositide-3 kinase (PI3K). These PIK3CA mutations most commonly occur concomitantly with the loss of adenomatous polyposis coli (APC). Copanlisib is a beta-isoform sparing PI3K inhibitor. Here we examine the response of CRCs with Apc and Pik3ca mutations to copanlisib alone and in combination with navitoclax, a BCL-2, BCL-xL, and BCL-w inhibitor.
Methods: Murine-derived organotypic cancer spheroids (MDOCS) with Apc and Pik3ca mutations generated from transgenic mice were cultured in Matrigel and treated by exchanging feeding media containing desired concentration of each agent over the spheroids. Spheroids were treated with feeding media (control), 200nM ABT263, 200nM copanlisib, or the combination of both treatments. The spheroid culture response was quantified as the median relative change in the sphere diameter, comparing pre- and posttreatment 4x optical microscopic images to those obtained 48 hours post-treatment.
Results: Untreated MDOCS had a median growth in sphere diameter of 137%. ABT263 did not significantly affect growth; however, copanlisib significantly reduced median sphere size by 24.6% (p<0.001) and the combination treatment reduced median sphere size by 33% which was significant to both control and copanlisib only treated spheres (p<0.001 and p=0.014, respectively). Phosphorylation of ribosomal protein S6 and 4EBP1 were suppressed with copanlisib treatment. Induction of apoptosis in these spheres treated with the combination regimen was confirmed with immunofluorescence for cleaved caspase 3 with minimal apoptosis observed in those spheres treated with copanlisib alone.
Conclusion: In this study, we demonstrated the ability of copanlisib alone and combined with ABT263 to cause a marked decrease in sphere size of CRC MDOCS with Apc and Pik3ca mutations. Future tests will examine this novel regimen in vivo and potentially in future clinical trials.
Citation Format: Devon D. Miller, Christopher P. Babiarz, Susan N. Payne, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Dustin A. Deming. Dual PI3K/BCL-2 family inhibition in colorectal cancers with Apc and Pik3ca mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 304.