Synergistic effect of alectinib and everolimus on anaplastic large cell lymphoma cells via ALK-mTOR pathway inhibition

Abstract

The purpose of this study was to investigate the synergistic effect of combination treatment of two drugs on ALK-positive cancer cells. The combination treat resulted in synergistic effect in Karpas299 cells but not in SU-DHL-1 cells. Viability of Karpas299 cell was decreased to 26.4% (p<0.001) by combination treatment of alectinib and everolimus compared with the single drug treated groups (alectinib: 59.5%, everolimus: 51.6%), and the value of Combination Index (CI) indicating synergism was 0.316. Moreover, combination treatment in Karpas299 augmented ALK-mTOR de-phosphorylation, and cleavage of poly ADP ribose polymerase (PARP) molecules. Combination treatment significantly increased the numbers of Karpas299 cells arrested at subG1 (everolimus: p= 0.0096), and G0/G1 (alectinib: p= 0.0018

everolimus: 0.0013). We further investigated the biological differences between Karpas299 and SU-DHL-1, the expression pattern of ALK isoforms (ALK-201 and 203) was different between the two cell lines. Overall, Combination treatment with alectinib and everolimus synergistically reduced cell survival, augmented inhibition of mTOR signaling, and increased cell cycle arrest in Karpas299 but not in SU-DHL1 cells. This set of results can suggest that the possibility of a novel combination treatment for ALK-positive lymphoma patients. It also provides an approach to developing new therapies.