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Series GSE227343 Query DataSets for GSE227343
Status Public on Sep 30, 2024
Title E7820, an Anti-Cancer Sulfonamide, Degrades RBM39 in Patients with Splicing Factor Mutant Myeloid Malignancies: A Phase II Clinical Trial
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Mutations in RNA splicing factor genes (SF3B1, SRSF2, and U2AF1) are common in AML and MDS and recent studies demonstrate pharmacologic degradation of the RNA splicing factor RBM39 results in preferential killing of splicing factor mutant cells. We therefore conducted a phase II clinical trial (NCT05024994) of the oral RBM39 degrader E7820 at the recommended phase II dose in patients with R/R MDS/AML and a splicing factor mutation. No patients met the primary endpoint of overall response rate in the first 12 patients enrolled, leading to study termination. However, E7820 was well-tolerated and achieved >50% RBM39 degradation in blood and disruption of splicing. At the same time, the degree of splicing disruption was far less than seen with in vitro doses exhibiting preclinical efficacy, providing potential explanation for limited clinical efficacy. Overall, this study demonstrates on-target safety and feasibility of RBM39 degradation in patients and supports future combination therapies with E7820.
 
Overall design Differential RNA splicing analysis by RNA-sequencing on human K562 or NKM1 cell lines (comparing treatment with E7820 or DMSO vehicle control) or cells derived from splicing factor mutated patients (comparing prior to initiation of E7820 clinical trial or on-trial) using single-replicates.
 
Contributor(s) Hogg SJ, Abdel-Wahab O
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Submission date Mar 14, 2023
Last update date Sep 30, 2024
Contact name Simon J Hogg
Organization name AbbVie
Department Oncology Discovery Research
Street address 1000 Gateway Boulevard
City South San Francisco
State/province California
ZIP/Postal code 94080
Country USA
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (29)
GSM7098137 PolyA_RNAseq_K562_parental_DMSO_24hours
GSM7098138 PolyA_RNAseq_K562_parental_E7820_24hours
GSM7098139 PolyA_RNAseq_K562_SF3B1-K700E_DMSO_24hours
Relations
BioProject PRJNA944678

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Supplementary file Size Download File type/resource
GSE227343_E7820_PolyA_RNAseq_raw_counts.csv.gz 1.8 Mb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record
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