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Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer [RNA-seq_siPRMT5]

ABSTRACT: CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236499 | GEO | 2023/07/11

REPOSITORIES: GEO

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Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer [RNA-seq_RBKO vs WT]

Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.

2023-07-11 | GSE236498 | GEO

Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer [RNA-seq_Pemrametostat]

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Protein arginine methyltransferase 5 (PRMT5) is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer [pSer2 Pol II ChIP-seq]

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RB-loss determines selective resistance and novel vulnerabilities in breast cancer modelsRB loss

Project description:The retinoblastoma tumor suppressor (RB1) plays a critical role in coordinating multiple pathways that impact on tumor initiation, disease progression, and therapeutic responses. Here we interrogated the effect of CDK4/6 inhibitor in combination with mTOR inhibtor. Also, we interrogtaed the efffect of AURK and WEE1 inhibition in ER+ breast cacner models While the RB-pathway has been purported to exhibit multiple mutually exclusive events, only RB1 is mutually exclusive with multiple genetic events that deregulate CDK4/6 activity. Using an isogenic ER+ breast cancer model with targeted RB1 deletion, we identified gene expression features that link CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). We also investigated the role of RB on apoptotic pathway. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, and is associated with reduced expression of multiple genes on 13q including RB1, and inversely related to the CDK4/6-RB integrated signature supporting a genetic cause/effect relationship. To probe the broader implications on tumor biology, we investigated genes that are positively and inversely correlated with the CDK4/6-RB integrated signature. This approach defined tumor-specific pathways that could represent new therapeutic vulnerabilities associated with RB-pathway activity.

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