mitoxantrone

The resulting splice site gene-edited clone, designated MX2/SS-Edit, expressed reduced TOP2α/160 mRNA/protein, increased TOP2α/170 mRNA/protein, and exhibited partial restoration of sensitivity to mitoxantrone, etoposide, and amsacrine. SIGNIFICANCE STATEMENT: Results presented here validated drug resistance in the HL-60/MX2 leukemia cell line driven by intronic polyadenylation (IPA) within intron 33 of the DNA topoisomerase IIα (TOP2α) gene, which produced a truncated and predominantly cytoplasmic TOP2α protein isoform (TOP2α/160). Using CRISPR/Cas9/homology-directed repair gene editing, the weak exon 33/intron 33 5' splice site was enhanced to suppress IPA, which restored expression of full-length protein (TOP2α/170) and led to a gain-of-function in drug sensitivity, offering a potential strategy to overcome drug resistance.

In addition, Mitoxantrone accumulation assay revealed a 1.4-fold increase, suggesting reduced ABCG2-mediated drug efflux. These findings support Venetoclax as a promising inhibitor of PIM1-mediated signalling with selective efficacy against aggressive breast cancer phenotypes. Its dual targeting of EMT signalling and drug resistance highlights its translational potential and paves the way for further clinical development.

This study reveals a critical in vitro and in vivo discordance and suggests that Mito + Doxo co-administration may paradoxically induce multidrug resistance, abrogating backbone chemotherapy efficacy. These findings urge caution in preclinical combination strategies involving standard-of-care agents and underscore the need for further investigation prior to clinical translation in ES.

P3, N=1645, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Sep 2027 --> Mar 2026

P3, N=276, Active, not recruiting, Astellas Pharma Inc | Trial completion date: Mar 2026 --> Mar 2027

P3, N=700, Recruiting, University of Birmingham | Active, not recruiting --> Recruiting

Drug interaction analyses assessed the combined effect of Selinexor and Mitoxantrone. E2F7-mediated HR inhibition is a key mechanism underlying Selinexor activity in AML. The XPO1-E2F7-HR axis represents a potential therapeutic vulnerability, supporting the rational combination of Selinexor with DNA-damaging agents to improve AML treatment outcomes.

P=N/A, N=300, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University; Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University

P=N/A, N=90, Completed, Tianjin First Central Hospital; Tianjin First Central Hospital

P3, N=700, Active, not recruiting, University of Birmingham | Recruiting --> Active, not recruiting

P1/2, N=62, Recruiting, University of Washington | Trial completion date: Dec 2027 --> Dec 2028 | Trial primary completion date: Dec 2026 --> Dec 2027

The patient underwent induction chemotherapy with cytarabine and mitoxantrone, followed by salvage therapy with venetoclax and azacitidine, resulting in morphologic remission. Subsequent haploidentical hematopoietic stem cell transplantation achieved remission, with ongoing hematologic recovery. This case underscores the limitations of conventional molecular assays in detecting cryptic fusions and highlights the critical role of comprehensive genomic profiling in refining subclassification and optimizing therapeutic strategies in pediatric AML.