Background Double/triple-hit lymphoma is an aggressive form of DLBCL with particularly poor outcome. XPO1 (exportin 1) is a well characterized nuclear export protein which is overexpressed in multiple tumor types. XPO1 exports many tumor-suppressor proteins and thus acts as a protooncogene by removing tumor suppressor protein and growth regulatory factors from the nucleus, where they are active, to the cytoplasm. First-in-class, single agent oral XPO1 inhibitor, Selinexor (ATG-010), was recently approved for the treatment of patients with DLBCL (de novo or transformed from follicular NHL) after at least two prior therapies. mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2) are critical mediators of the PI3K-AKT pathway. Signaling by the PI3K/AKT/mTOR pathway is frequently deregulated in NHL. Inhibition of mTOR has shown preclinical and clinical efficacy in treating DLBCL. This study tested the antitumor effects induced by the combination of the XPO1 inhibitor, Selinexor and the dual mTORC1/2 kinase inhibitor, ATG-008 (Onatasertib) on triple-hit DLBCL cells, DoHH2.

Methods Firstly, the in vitro 50% inhibition concentration (IC50) of two compounds was determined in DoHH2 cell line using CellTiter-Glo luminescent cell viability assay. The synergy effect of compound ATG-008 in combination with ATG-010 were evaluated by combination index (CI). The synergy effect is calculated by the Chou-Talalay Method [1]. The CI score ranging from 0.1-0.9 suggests very strong to slight synergism. The in vivo combination of the drugs were tested in DoHH2 CDX mouse model. The tumor bearing mouse were treated with vehicle control, Selinexor (5mg/kg, MWF), ATG-008 (10mg/kg, QD) or the combination for 21 days. The tumor size was measured twice a week and tumor growth inhibition (TGI) was evaluated compared with vehicle control group.

Results Potent in vitro and in vivo anti-tumor efficacy and synergy has been observed for the combination of the two drugs. The in vitro IC50 for DOHH-2 cell line were 0.85µM and 0.08µM for ATG-008 and Selinexor, respectively. Synergy has been observed for most combo concentrations tested with the strongest synergism observed for ATG-008 (1.7µM) + Selinexor (0.16µM). The combination index was 0.48. In the DoHH2 CDX in vivo study, the mono therapy of ATG-008 showed 41% TGI at day 19 after grouping (p value<0.001), and 19% TGI for Selinexor (p value= 0.147) mono therapy treatment group. The combination of ATG-008 and Selinexor showed 75% TGI (p value<0.01).

Conclusions Strong synergism has been observed for the combination of XPO1 and mTORC1/2 inhibition by Selinexor and ATG-008, respectively, suggesting promising therapeutic strategies for double/triple-hit lymphoma patients that warrants further investigation. [1]Chou TC. Cancer Res. 2010 Jan 15;70(2):440-6.

Citation Format: Bing Hou, Aihua Wang, Bo Shan, Jay Mei. Synergistic effect of the combination of XPO1 and mTORC1/2 inhibition for the treatment of triple-hit DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1380.