The Novel Calcium Release-Activated Calcium (Crac) Channel Inhibitor Rp4010 Exerts Potent Antitumor Effects In Nod/Scid/Il2rg(-/-) Mice With Diffuse Large B Cell Lymphoma (Dlbcl) Cell Line Xenografts

INTRODUCTION: Calcium ions (Ca2+) act as second messengers in cell signaling triggering various cellular processes, including gene transcription, secretion, cell proliferation, migration, and apoptosis. Store-operated Ca2+ entry (SOCE) is activated by Ca2+ release from the endoplasmic reticulum. Two genes are responsible for SOCE activity: Stromal interaction molecule 1 (STIM1), an ER Ca2+ sensor that detects store depletion and Orai1, the pore-forming subunit of Ca2+ release-activated Ca2+ (CRAC) channel. Downregulation of Orai1, and consequently SOCE, protects the cells from diverse apoptosis-inducing pathways. As emerging evidence points to the involvement of aberrant CRAC channel activity in human diseases including Diffuse Large B Cell Lymphoma (DLBCL), we hypothesize that the CRAC channel inhibitorRP4010 might represent a unique therapeutic opportunity for DLBCL patients. RP4010 is a potent inhibitor of CRAC channel activity (IC50=60 nM) with demonstrated efficacy across a range of cancer cell lines in vitro . This study aimed at investigating the activity of RP4010 in preclinical DLBCL models.