New drug combinations for patients with myelodysplastic syndromes (MDS) could be developed thanks to new research which has uncovered the underlying mechanisms of certain gene mutations in the disorder.
The study, from researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, USA, was presented at the American Society of Hematology’s annual meeting in San Diego, USA in December 2023.
Although about half of MDS patients carry somatic mutations in the spliceosome genes, with SF3B1 being the most common one, there is no successful therapy to target this pathway, the researchers say.
Previous findings from a phase 2 clinical trial of selinexor, an Exportin-1 (XPO1) inhibitor for relapsed or refractory MDS, showed increased effectiveness in patients with SF3B1-mutated MDS.
Sylvester researchers and collaborators hypothesised that inhibiting XPO1 may preferentially affect SF3B1-mutant cells via altered splicing. They believe that high-risk MDS patients with this mutation would have a better response to dose-controlled, targeted drug combinations with next-generation XPO1 inhibitors.
For this study, the researchers examined RNA sequencing to evaluate the underlying mechanism for the SF3B1 mutation’s sensitivity to XPO1 inhibitors. The team also conducted whole genome CRISPR screens in two myeloid leukaemia cell lines with eltanexor, a next-generation XPO1 inhibitor. This work eventually identified strong synergy between eltanexor and two drugs – venetoclax and navitoclax. Further in vitro and in vivo studies validated these combinations.
Sana Chaudhry, Sylvester researcher, told the conference: “This is the first study to examine the effects of XPO1 inhibition on RNA export to better understand the underlying mechanisms involved with the most common mutation seen in MDS patients.”
It is hoped the findings may lead to the development of synergistic therapeutic combinations to better treat SF3B1-mutant MDS.
Recent data from human studies found venetoclax can overcome the poor prognosis often associated with acute myeloid leukaemia (AML) patients with mutations, which means combining eltanexor with venetoclax could be a potentially effective SF3B1-specific therapy, the conference heard.
Chaudhry S, Beckedorff F, Totiger TM, Affer M, Hariramani N, Montoya S, Cornista A, Bilbao D, Roberts ER, Afaghani J, Rodríguez JA, Wang E, Taylor T (2023) “Altered RNA Export in SF3B1 Mutants Increases Sensitivity to Nuclear Export Inhibition.”, presentation at American Society of Hematology’s Annual Meeting, Santa Diego, USA, December 2023
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