Dataset Information

Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells.

ABSTRACT: Rhabdoid tumors (RT) are rare and deadly pediatric cancers driven by loss of SMARCB1, which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Loss of SMARCB1 is associated with a complex set of phenotypic changes including vulnerability to inhibitors of protein synthesis and of the p53 ubiquitin-ligase HDM2. Recently, we discovered small molecule inhibitors of the 'WIN' site of WDR5, which in MLL-rearranged leukemia cells decrease the expression of a set of genes linked to protein synthesis, inducing a translational choke and causing p53-dependent inhibition of proliferation. Here, we characterize how WIN site inhibitors act in RT cells. As in leukemia cells, WIN site inhibition in RT cells causes the comprehensive displacement of WDR5 from chromatin, resulting in a decrease in protein synthesis gene expression. Unlike leukemia cells, however, the growth response of RT cells to WIN site blockade is independent of p53. Exploiting this observation, we demonstrate that WIN site inhibitor synergizes with an HDM2 antagonist to induce p53 and block RT cell proliferation in vitro. These data reveal a p53-independent action of WIN site inhibitors and forecast that future strategies to treat RT could be based on dual WDR5/HDM2 inhibition.

SUBMITTER: Florian AC

PROVIDER: S-EPMC8892060 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells.

Florian Andrea C AC Woodley Chase M CM Wang Jing J Grieb Brian C BC Slota Macey J MJ Guerrazzi Kiana K Hsu Chih-Yuan CY Matlock Brittany K BK Flaherty David K DK Lorey Shelly L SL Fesik Stephen W SW Howard Gregory C GC Liu Qi Q Weissmiller April M AM Tansey William P WP

NAR cancer 20220303 1

Rhabdoid tumors (RT) are rare and deadly pediatric cancers driven by loss of <i>SMARCB1</i>, which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Loss of <i>SMARCB1</i> is associated with a complex set of phenotypic changes including vulnerability to inhibitors of protein synthesis and of the p53 ubiquitin-ligase HDM2. Recently, we discovered small molecule inhibitors of the 'WIN' site of WDR5, which in MLL-rearranged leukemia cells decrease the expression of a set of genes linke ...[more]

PMID: 35252869

Similar Datasets

Project description:SMARCB1 biallelic inactivation resulting in SMARCB1/INI1 deficiency drives a wide range of malignancies, including many mesenchymal tumors. However, the specific types of SMARCB1 alterations and spectrum of cooperating mutations among various types of sarcomas has not been well investigated. We profiled SMARCB1 genetic alterations by targeted DNA sequencing and fluorescence in situ hybridization (FISH) in a large cohort of 118 soft tissue and bone tumors, including SMARCB1-deficient sarcomas (78, 66%): epithelioid sarcomas, epithelioid peripheral nerve sheath tumors, poorly differentiated chordomas, malignant rhabdoid tumors, and soft tissue myoepithelial tumors, as well as non-SMARCB1-deficient sarcomas (40, 34%) with various SMARCB1 genetic alterations (mutations, copy number alterations). SMARCB1 loss by immunohistochemistry was present in 94% SMARCB1 pathogenic cases. By combined sequencing and FISH assays, 80% of SMARCB1-deficient tumors harbored homozygous (biallelic) SMARCB1 loss, while 14% demonstrated heterozygous SMARCB1 loss-of-function (LOF) alterations, and 6% showed no demonstrable SMARCB1 alterations. FISH and sequencing were concordant in the ability to detect SMARCB1 loss in 48% of cases. Epithelioid sarcomas most commonly (75%) harbored homozygous deletions, while a subset showed focal intragenic deletions or LOF mutations (nonsense, frameshift). In contrast, most soft tissue myoepithelial tumors (83%) harbored SMARCB1 nonsense point mutations without copy number losses. Additionally, clinically significant, recurrent co-occurring genetic events were rare regardless of histotype. By sequencing, extended 22q copy number loss in genes flanking the SMARCB1 locus (22q11.23) occurred in one-third of epithelioid sarcomas and the majority of poorly differentiated chordomas. Poorly differentiated chordomas and soft tissue myoepithelial tumors showed significantly worse overall and disease-free survival compared to epithelioid sarcomas. Overall, SMARCB1 LOF alterations predominate and account for SMARCB1 protein loss in most cases: majority being biallelic but a subset were heterozygous. In contrast, SMARCB1 alterations of uncertain significance can be seen in diverse sarcomas types and does not indicate a SMARCB1-deficient entity.

Project description:In the present study, a 36-year-old male presented with left scrotal enlargement without an obvious cause, accompanied by a feeling of heaviness. Imaging examinations revealed a left testicular malignancy, the patient underwent left testicular mass removal,and the postoperative pathology results revealed a highly malignant germ cell tumor, with a tendency toward poorly differentiated embryonal carcinoma or seminoma. After surgery, the condition of the patient deteriorated rapidly, and distant tumor metastasis occurred. Lymph node puncture pathology results revealed poorly differentiated carcinoma consistent with SMARCB1/INI-1 deletion. Despite the use of chemotherapy, radiotherapy, immunotherapy and targeted therapy, the patient died 11 months after surgery. To the best of our knowledge, this is the first case report of a SMARCB1/INI1-deficient Poorly differentiated testicular carcinoma, which is very similar to testicular spermatocytic carcinoma in clinical diagnosis and deserves differentiation for future clinical diagnoses.This report provides important insights into the diagnosis and treatment of SMARCB1/INI1-deficient testicular malignancy. SMARCB1 is a crucial tumor suppressor gene, and its deficiency is closely associated with the development of various malignant tumors. The identification of this case suggests that future research should further explore the molecular mechanisms of SMARCB1-deficient tumors, particularly their role in testicular malignancies. Additionally, the diagnostic process of this case highlights that SMARCB1/INI1-deficient tumors can be clinically very similar to spermatocytic carcinoma of the testis, which can easily lead to misdiagnosis. Therefore, future clinical practice should emphasize the detection of SMARCB1/INI1 expression status, especially in the context of highly aggressive and rapidly progressing testicular malignancies, where immunohistochemical testing for SMARCB1/INI1 should be considered to confirm the diagnosis. In terms of treatment, this case demonstrates the highly aggressive nature and resistance to conventional therapies of SMARCB1/INI1-deficient tumors. Despite the patient receiving multiple treatments, disease progression could not be halted. This underscores the need for the development of novel therapeutic strategies targeting SMARCB1/INI1-deficient tumors, such as combinations of immune checkpoint inhibitors and targeted therapies, or other emerging immunotherapeutic approaches. Moreover, the treatment course of this patient also reflects the importance of individualized treatment plans. Future research should further explore precision medicine strategies based on tumor genetic profiles to improve patient survival rates and quality of life.

Project description:Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dataset Information

Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells.

Publications

Synergistic action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets