XPO1 drives resistance to eprenetapopt and azacitidine and can be targeted in <i>TP53</i> -mutated myeloid malignancies
Abstract
Abstract TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are among the most aggressive and chemotherapy-refractory myeloid neoplasms, with a median overall survival of &lt;6 months. An enormous unmet need exists to develop novel therapeutic strategies, and understand resistance mechanisms to suboptimal existing therapies for this disease. In 2 parallel, phase 2 clinical trials that combined eprenetapopt with azacitidine in TP53-mutated MDS/AML, we observed complete remission rates of 40% to 50%, and molecular remission rates of 38%. However, unless allogeneic stem cell transplant was performed, relapse inevitably occurred. To understand the mechanisms of secondary resistance responsible for this, we genotyped sequential clinical trial samples, conducted a genome-wide CRISPR screen in TP53-mutated leukemia cells, and identified XPO1 as a therapeutically tractable mediator of resistance. We demonstrate that XPO1 is overexpressed in patient samples after eprenetapopt and azacitidine treatment, elucidate the mechanism by which this occurs, and determine that it is necessary and sufficient for resistance to combination therapy. Finally, we validate in a variety of model systems, including a novel patient-derived xenograft model of TP53 mutant MDS, that eprenetapopt in combination with XPO1 inhibitors can overcome this resistance, providing preclinical rationale that this novel combination strategy is a viable therapeutic approach in patients with TP53 mutant MDS/AML.
Article Details
Authors (21)
Traci L. Kruer
1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL
Ariel Quintana
1H Lee Moffitt Cancer Center, Clinical Science, Tampa, United States
Hannah Newman
1H Lee Moffitt Cancer Center, Clinical Science, Tampa, United States
Meghan Ferrall-Fairbanks
4University of Florida, Gainesville, United States
Ling Zhang
Amy McLemore
1Moffitt Cancer Center, Tampa, United States
Surendra Neupane
1Moffitt Cancer Center, Tampa, United States
Qin Yang
Department of Chemical and Biomolecular Engineering
Nana Adjoa Dankyi
1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL
Maria E. Balasis
1Department of Clinical Science, Moffitt Cancer Center, Tampa, FL
Christopher Letson
1Washington University School of Medicine, Saint Louis, United States
Rami Komrokji
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Sana Chaudhry
4Division of Hematology, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, FL
Tulasigeri M. Totiger
4Division of Hematology, Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami, FL
Joshua Traina
1Moffitt Cancer Center, Tampa, United States
Maria E. Figueroa
6Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Division of Hematology, Miami, United States
Christopher B. Ryder
3Department of Pathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL
Thomas Cluzeau
15Service d’Hématologie, Centre Hospitalier Universitaire de Nice, Nice, France
Justin Taylor
David A. Sallman
6Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
Eric Padron
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States