Targeting the DNA damage response through TBL1X in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma characterized by significant genomic instability. Patients with MCL who progress on targeted therapies have a short survival; thus, novel therapeutic strategies are urgently needed. Overexpression of transducin β-like protein 1 X-linked (TBL1X) has been documented in several types of cancer and associated with poor prognosis. TBL1X is a critical regulator of multiple oncogenic networks; however, its function in MCL has not been explored. Our data show that, unlike normal B cells, MCL cells express abundant levels of TBL1X and that genetic knockdown of TBL1X and treatment with tegavivint (Iterion), a first-in-class small molecule targeting TBL1X, promote MCL cell death in vitro and in vivo. Moreover, TBL1X controls the stability of key MCL oncogenic drivers, cyclin D1 and RAD51; and targeting TBL1X results in significant DNA damage, cell cycle arrest, and ultimately cell death. Combining tegavivint with poly(adenosine 5'-diphosphate-ribose) polymerase-1/2 inhibitor talazoparib results in synergistic MCL cell death in vitro, and in vivo this combination significantly prolongs the survival of a patient-derived MCL xenograft. Together, our results define the role of TBL1X in maintaining genomic stability in MCL and establish targeting TBL1X as a novel therapeutic strategy for patients with this incurable disease.