Abstract 3934: PRMT5 is an actionable target in CDK4/6 inhibitor-resistant ER+/Rb-deficient breast cancer
Bibliographic record
Abstract
Abstract RB1 loss-of-function genomic alterations confer resistance to CDK4/6 inhibitors (CDK4/6i) and are enriched post treatment of CDK4/6i in estrogen receptor-positive (ER+) metastatic breast cancer. ER+/Rb-deficient breast cancer is a rising patient population in need of novel therapeutic strategies. Herein, we used a genome-wide CRISPR screen and identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in this refractory breast cancer subtype. sgRNA-induced depletion of PRMT5 arrested growth of MCF-7 and T47D RB1 knockout (RBKO) cells. PRMT5 catalyzes symmetric dimethylation of arginine (SDMA). In RBKO cells carrying doxycycline-inducible shRNA targeting the 3’UTR of PRMT5, rescue with wild-type but not an enzymatically dead mutant of PRMT5 restored cell growth, supporting that PRMT5 methyltrasferase activity is essential for growth of these cells. Gene set enrichment analysis (GSEA) of RNA-seq data revealed significant downregulation of cell cycle-related Hallmark gene signatures in RBKO cells treated with PRMT5 siRNA versus control siRNA. Both gene silencing and pharmacological blockade of PRMT5 with the small molecule inhibitor pemrametostat impeded G1-to-S cell cycle progression in MCF-7 and T47D RBKO cells and in lung, prostate, and triple-negative breast cancer cells with natural RB1 mutations or deletions, suggesting that PRMT5 inhibition can block the G1-to-S transition even in the absence of Rb. To identify the protein interactome of PRMT5 and the mechanism by which it promotes cell cycle progression in Rb-deficient cells, we performed proteomics analysis of Co-IP mass spectrometry and an SDMA post-translational modification scan and pinpointed FUS (fused in sarcoma) as a putative downstream effector of PRMT5. FUS is known to regulate RNA polymerase II (Pol II)-mediated transcription. Inhibition of PRMT5 with pemrametostat significantly reduced SDMA levels on FUS and dissociated FUS from Pol II as evidenced by FUS Co-IP and immunoblot analysis. ChIP-seq analysis revealed that treatment of RBKO cells with pemrametostat derepressed phosphorylation of Ser2 in the C-terminus of Pol II at transcription start sites (TSS) of genes involved in cell cycle progression. In accordance with the abnormal accumulation of pSer2 Pol II at TSS, pemrametostat treatment also resulted in an increased Pol II pausing index and an enrichment of intron retention splicing variants. Finally, therapeutic inhibition of PRMT5 with pemrametostat synergized with fulvestrant (a selective ER degrader) against growth of ER+/Rb-deficient breast cancer cell line- and patient-derived xenografts in mice, suggesting this combination as a novel therapeutic strategy for ER+/Rb-deficient metastatic breast cancers. Citation Format: Chang-Ching Lin, Tsung-Cheng Chang, Yunguan Wang, Yanfeng Zhang, Andrew Lemoff, Yisheng V. Fang, He Zhang, Dan Ye, Isabel Soria-Bretones, Alberto Servetto, Kyung-min Lee, Xuemei Luo, Joseph J. Otto, Hiroaki Akamatsu, David W. Cescon, Lin Xu, Yang Xie, Joshua T. Mendell, Ariella B. Hanker, Carlos L. Arteaga. PRMT5 is an actionable target in CDK4/6 inhibitor-resistant ER+/Rb-deficient breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3934.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".