Targeting the DNA Damage Response through TBL1X in Mantle Cell Lymphoma

• TBL1X plays a multifaceted role in promoting the proliferation and survival of mantle cell lymphoma cells.

• Targeting TBL1X promotes destabilization of cyclin D1 and RAD51, resulting in cell cycle arrest, DNA damage, and MCL cell death.

Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma characterized by significant genomic instability. MCL patients 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 PARP-1/2 inhibitor talazoparib results in synergistic MCL cell death in vitro, and in vivo this combination significantly prolonging the survival of an MCL PDX. 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.