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Combination of the MTA-Cooperative PRMT5 Inhibitor BMS-986504 and KRAS Inhibitors Is an Effective Treatment Strategy
Kristina Drizyte-Miller1, Lars D Engstrom2, Jeffrey A Klomp3
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in MTAP-deleted (MTAP-del) cancers. The MTA-cooperative PRMT5 inhibitor BMS-986504 exhibited potent and selective antitumor activity in MTAP-del preclinical models and demonstrated activity in MTAP-del patients without the toxicity associated with previous PRMT5 inhibitors. In this study, we focused on pancreatic ductal adenocarcinoma (PDAC), ∼22% of which are MTAP-del, and demonstrated that BMS-986504 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models. CRISPR/Cas9 loss-of-function screens implicated cotargeting KRAS as a combination strategy. Concurrent inhibition of PRMT5 and KRASG12C/D enhanced and prolonged suppression of PDAC growth. RNA sequencing analysis revealed that PRMT5 inhibition disrupted RNA splicing of genes essential for PDAC growth. Although PRMT5 and KRAS regulated distinct transcriptomes, they converged on pathways governing cancer cell growth and expression of PDAC-essential genes. These findings provide rationale for combined inhibition of PRMT5 and KRAS in MTAP-del/KRAS-mutant PDAC.
Significance:
MTAP deletion and mutational activation of KRAS create therapeutic vulnerabilities for MTA-cooperative PRMT5 and mutant-selective KRAS inhibitors, respectively, providing the rationale for their combination therapy for MTAP-deleted, KRAS-mutant pancreatic cancer. See related article by Knoll et al., p. 3518.
Insights
Protein arginine methyltransferase 5 (PRMT5) inhibition shows promise for MTAP-deleted cancers. Combining PRMT5 and KRAS inhibition effectively targets pancreatic ductal adenocarcinoma, enhancing anti-tumor effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine triphosphatase (MTAP)-deleted (MTAP-del) cancers.
- BMS-986504, a PRMT5 inhibitor, demonstrates potent anti-tumor activity in preclinical models and patients with MTAP-del cancers, with reduced toxicity compared to earlier inhibitors.
Purpose of the Study:
- To investigate the efficacy of BMS-986504 in pancreatic ductal adenocarcinoma (PDAC), a cancer with a significant proportion of MTAP-del cases.
- To explore combination strategies, specifically co-targeting PRMT5 and KRAS, for enhanced therapeutic effects in MTAP-deleted PDAC.
Main Methods:
- Utilized CRISPR/Cas9 loss-of-function screens to identify potential combination therapies.
- Administered BMS-986504 to MTAP-del PDAC cells and xenograft models.
- Performed RNA-sequencing to analyze the molecular effects of PRMT5 inhibition.
Main Results:
- BMS-986504 effectively suppressed PRMT5 function and growth in MTAP-del PDAC models.
- Concurrent inhibition of PRMT5 and KRAS (specifically KRASG12C/D) led to enhanced and prolonged suppression of PDAC growth.
- PRMT5 inhibition disrupted RNA splicing of critical genes, impacting PDAC cell growth pathways.
Conclusions:
- Combined inhibition of PRMT5 and KRAS presents a promising therapeutic strategy for MTAP-deleted and KRAS-mutant PDAC.
- PRMT5 and KRAS inhibition converge on key pathways regulating cancer cell growth and gene expression in PDAC.
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