1. Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.
- Author
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Howard GC, Wang J, Rose KL, Jones C, Patel P, Tsui T, Florian AC, Vlach L, Lorey SL, Grieb BC, Smith BN, Slota MJ, Reynolds EM, Goswami S, Savona MR, Mason FM, Lee T, Fesik S, Liu Q, and Tansey WP
- Subjects
- Humans, Antineoplastic Agents pharmacology, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Cell Line, Tumor, Histone-Lysine N-Methyltransferase metabolism, Histone-Lysine N-Methyltransferase genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Peptidomimetics pharmacology, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Myeloid-Lymphoid Leukemia Protein metabolism, Myeloid-Lymphoid Leukemia Protein genetics, Nuclear Proteins metabolism, Nuclear Proteins genetics, Ribosomes drug effects, Ribosomes metabolism, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics
- Abstract
The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies., Competing Interests: GH, JW, KR, CJ, PP, TT, AF, LV, SL, BG, BS, MS, ER, SG, FM, QL No competing interests declared, MS Receives research funding from ALX Oncology, Astex, Incyte, Takeda and TG Therapeutics; has stock in Karyopharm and Ryvu; serves on advisory boards or consults for BMS, CTI, Forma, Geron, GSK, Karyopharm, Rigel, Ryvu, Taiho and Treadwell, TL, SF Patents: Lee T, Alvarado J, Tian J, Meyers KM, Han C, Mills JJ, Teuscher KB, Stauffer SR, Fesik SW. WDR5 inhibitors and modulators. WO 2020086857. 30 April 2020; Lee T, Han C, Mills JJ, Teuscher KB, Tian J, Meyers KM, Chowdhury S, Fesik SW. WDR5 inhibitors and modulators. WO 2020247679. 10 December 2020; Lee T, Teuscher KB, Tian J, Meyers KM, Chowdhury S, Fesik SW. WDR5 Inhibitors and modulators. WO 2021092525. 14 May 2021; Lee T, Teuscher KB, Chowdhury S, Tian J, Meyers KM, Fesik SW. WDR5 Inhibitors and modulators. WO2022236101. 10 November 2022, WT Patents: Fesik SW, Stauffer SR, Salovich JM, Tansey WP, Wang F, Phan J, Olejniczak ET, inventors. WDR5 inhibitors and modulators. United States Patent US 10,501,466. 10 December 2019; Fesik SW, Stauffer SR, Tansey WP, Olejniczak ET, Phan J, Wang F, Jeon K, Gogliotti RD, inventors. WDR5 inhibitors and modulators. United States Patent US 10,160,763. 25 December 2018, (© 2023, Howard et al.)
- Published
- 2024
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