Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS and AML

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Splicing modulation is an emerging cancer therapy, primarily studied in splicing factor-mutant cancers.
• Cohesin complex gene mutations are common in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), correlating with poor prognosis.
• The therapeutic potential of splicing modulation in cancers with cohesin mutations remains largely unexplored.

Purpose of the Study:

• To investigate the therapeutic potential of splicing factor 3B subunit 1 (SF3B1) modulators in cohesin-mutant cancers.
• To identify biomarkers predicting sensitivity to SF3B1 modulators.
• To elucidate the mechanism of action for SF3B1 modulators in cohesin-mutant cancer models.

Main Methods:

• Utilized cell line models, primary patient samples, and patient-derived xenograft (PDX) models of AML.
• Administered SF3B1 modulators (H3B-8800, E-7107) to assess drug-induced splicing alterations and gene expression changes.
• Evaluated DNA repair gene expression, DNA damage response, sensitivity to PARP inhibitors and chemotherapy, and overall survival in vivo.

Main Results:

• Cohesin mutations identified as biomarkers for sensitivity to SF3B1 modulators.
• SF3B1 modulators induced alterations in splicing and reduced expression of DNA repair genes, including BRCA1 and BRCA2.
• DNA damage repair genes showed particular sensitivity to SF3B1 modulator-induced exon skipping.
• SF3B1 modulator treatment impaired DNA damage response, increased DNA damage accumulation, and sensitized cohesin-mutant cells to PARP inhibitors and chemotherapy.
• Improved overall survival observed in PDX models of cohesin-mutant AML treated with SF3B1 modulators.

Conclusions:

• SF3B1 splicing modulators demonstrate therapeutic potential beyond splicing factor-mutant cancers, extending to cohesin-mutant MDS and AML.
• Cohesin mutations serve as predictive biomarkers for SF3B1 modulator therapy.
• Targeting splicing offers a novel strategy to enhance DNA damage repair inhibition and improve treatment outcomes in specific hematological malignancies.