Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia
Holly Pariury,
Joshua Fandel,
Stefanie Bachl,
Kenny K. Ang,
Sarine Markossian,
Chris G. Wilson,
Benjamin S. Braun,
Bogdan Popescu,
Margo Wohlfeil,
Kyle Beckman,
Simayijiang Xirenayi,
Ritu P. Roy,
Adam B. Olshen,
Catherine Smith,
Michelle R. Arkin,
Mignon L. Loh,
Ernesto Diaz-Flores
Affiliations
Holly Pariury
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; CA; Department of Pediatrics, Banner University Medical Center and the University of Arizona Cancer Center, Tucson; AZ
Joshua Fandel
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Stefanie Bachl
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Kenny K. Ang
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California
Sarine Markossian
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California
Chris G. Wilson
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California
Benjamin S. Braun
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Bogdan Popescu
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco
Margo Wohlfeil
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Kyle Beckman
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Simayijiang Xirenayi
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Ritu P. Roy
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco
Adam B. Olshen
Computation Biology and Informatics Core at the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; CA; Department of Epidemiology and Biostatistics, University of California
Catherine Smith
Division of Hematology/Oncology, Department of Medicine, University of California San Francisco
Michelle R. Arkin
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California
Mignon L. Loh
Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute; Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA
Ernesto Diaz-Flores
Department of Pediatrics, Benioff Children’s Hospital, and the Helen Diller Family Comprehensive Cancer Center, University of California
Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-lineage ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a highthroughput drug screen, we identified dinaciclib, a cyclin-dependent kinase inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL patient-derived xenografts mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.
