| Autor: |
Zablonski KG; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Skupa SA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Eiken AP; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Sundaram S; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Mavis C; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Gu JJ; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Torka P; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Ghione P; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., El-Gamal D; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA., Hernandez-Ilizaliturri FJ; Departments of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. |
| Abstrakt: |
Chronic lymphocytic leukemia (CLL) remains incurable and its ability to acquire resistance to front-line therapeutics has proved challenging. Bromodomain and extra-terminal proteins, particularly bromodomain-containing protein 4 (BRD4), are integral to gene expression in CLL and offer a promising therapeutic target. In this study, we examined the activity of the BRD4 inhibitor OPN-51107 alone and in combination with the BCL-2 inhibitor, venetoclax, in CLL cell lines and patient-derived CLL samples. We demonstrate that OPN-51107 induces anti-tumor activity in both CLL cell lines and patient-derived samples, including relapsed/refractory (R/R) samples and those with high-risk features (i.e. ATM and/or TP53 deletions). Importantly, the combination of OPN-51107 and venetoclax exhibited synergistic cytotoxicity in ibrutinib-resistant CLL cells and patient-derived CLL samples regardless of R/R or deletion status. This study establishes the preclinical efficacy of using OPN-51107 and venetoclax in combination in therapy-resistant and/or high-risk CLL, lending support for its further development as a combination therapy. |
