OCI-LY-19

Combinations With BET Inhibitors and LRRK2 as a Novel Putative Target in Lymphoma

Inhibitors of the Bromo- and Extra-Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. The combination between LRRK2-IN-1 and birabresib was also evaluated using the efficacy and potency parameter (CIT) according to the MuSyC algorithm, showing additivity in efficacy and between additivity and synergism in the potency parameter in all the cell lines tested.

To uncover the importance of LRRK2 protein in the growth of GCB DLBCL cell lines (OCI-LY-19 and WSU-DLCL2), a silencing of LRRK2 by siRNAs was performed. LRRK2 silencing affected the cell growth causing a reduction in cell growth after 48 h of silencing (Fig. 1A-C). Total and phosphorylated GSK3β and AKT proteins were analyzed, due to their possible association with the function of LRRK2. LRRK2 silencing led to a downregulation of p-AKT (S473) and p-GSK3β (S9) levels (Fig. 2). The effect on cell proliferation after LRRK2 silencing was increased when LRRK2 siRNAs were combined with the BET inhibitor birabresib. There was a beneficial effect on the proliferation between LRRK2 silencing and birabresib treatment in OCI-LY-19 (48 h) (Fig. 2A). LRRK2 silencing was performed with four individual siRNAs present in the pool. A consistent reduction of proliferation compared to control siRNAs was increased when combined with birabresib (Fig. 2D).

Fig. 1 LRRK2 is important for lymphoma cell lines (OCI-LY-19 and WSU-DLCL2). (Spriano F, et al., 2022)

Fig. 2 Birabresib improves the LRRK2 silencing effect in OCI-LY-19. (Spriano F, et al., 2022)