Expression data from Rhabdomyosarcoma human cells treated with Ipatasertib or Miransertib.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE268191 | GEO | 2025/07/16
REPOSITORIES: GEO
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Project description:Rhabdomyosarcoma (RMS) is marked by a myogenesis differentiation blockade, and while the AKT/mTOR pathway is universally activated, its pharmacological inhibition has shown limited success. This study stems from an effort to understand the failure to translate preclinical findings to clinical application. Here, we evaluated the activity of two pan-AKT inhibitors: Ipatasertib, an ATP-competitive inhibitor, and Miransertib, an allosteric AKT inhibitor. In vitro and in vivo efficacy assessment was conducted in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). Unlike Miransertib, Ipatasertib showed significant antitumor activity against a subset of RMS. Besides AKT, the other kinase target of Ipatasertib, but not of Miransertib, is PRKG1, a cGMP-dependent protein kinase that shares the ATP binding pocket with AKT. The role of PRKG1 in RMS was investigated in PRKG1-depleted RMS cells and in xenograft models by transcriptomic approaches. PRKG1 silencing in RMS cells reduced tumor formation in xenograft models and induced a differentiated myogenic transcriptome. RMS showed higher PRKG1 expression compared to any other developmental cancer, akin to fetal skeletal muscle. Importantly, PRKG1 expression in RMS correlates with mesodermal transcriptional signature and enhanced sensitivity to Ipatasertib, regardless of the fusion oncogene status. The antitumor activity of Ipatasertib is dose-dependent, reaching an effective intra-tumor concentration when administered at 25 mg/kg daily. This study unveils the role of PRKG1 in myogenesis and highlights the potential of PRKG1 as a clinical biomarker for Ipatasertib therapy in RMS.
2025-07-16 | PXD064262 | Pride
Project description:SUM149PT cell line treated with AKTi (ipatasertib) and EZH2i (tazemetostat).
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Project description:Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by a fusion protein (e.g. PAX3-FOXO1) or by mutations in key signalling molecules (e.g. RAS or FGFR4). Despite the latter giving potential for precision medicine approaches in RMS, there are no such treatments implemented in the clinic yet. In order to identify and test novel precision therapy strategies, appropriate cellular and mouse models are crucial. We have here thoroughly characterized a RMS patient-derived cell line model, RMS559, which harbours a FGFR4 V550L activating mutation with high allelic frequency (0.8). Importantly, we show that RMS559 cells are oncogenically dependent on FGFR4 signalling by treatment with the pan-FGFR inhibitor LY2874455. Phosphoproteomic analysis identified RAS/MAPK and PI3K/AKT as the major druggable signalling pathways downstream of FGFR V550L. Inhibitors against these pathways inhibited cell proliferation. Furthermore, we found that FGFR4 V550L is dependent on HSP90 and inhibitors targeting HSP90 efficiently restrain proliferation. Recently, FGFR4 specific inhibitors have been developed. While two of these, BLU-9931 and H3B-6527, did not efficiently inhibit FGFR4 V550L, probably because of the gatekeeper mutation (V550L), one of them, FGF401 inhibited FGFR4 V550L and cell proliferation at low nanomolar concentrations. Finally, we developed a mouse model using RMS559 cells and tested the in vivo efficacy of LY2874455 and FGF401. While LY2874455 inefficiently inhibited growth, FGF401 completely abrogated tumour growth in vivo.
2022-10-19 | PXD029719 | Pride
Project description:Expression data from Rhabdomyosarcoma human cells treated with Ipatasertib or Miransertib.
| PRJNA1115079 | ENA
Project description:Rhabdomyosarcoma (RMS) presents a significant challenge in the field of oncology as a high-grade, aggressive soft tissue sarcoma that originates from skeletal (striated) muscle cells which do not fully differentiate. This condition is characterized by two major molecular and histopathological subtypes: 'alveolar' RMS (ARMS) and 'embryonic' RMS (ERMS), each driven by unique underlying mechanisms. The disease's inherent heterogeneity, complex genetic makeup, and limited therapeutic options highlight the need for innovative research approaches to understand its complexities. Through the use of transcriptomics, alongside an exploration of proteomics, researchers have identified dysregulated proteins common to both subtypes, offering insights into the pathophysiology and aggressiveness of RMS. Additionally, metabolomics sheds light on metabolic pathways linked to RMS perturbation. The integration of high-throughput omics ‘Multi-omics’ technologies thus provides unprecedented opportunities to dissect the molecular intricacies of cancer biology, offering avenues for enhanced understanding and targeted interventions in RMS.
2025-08-04 | PXD052488 | Pride
Project description:To explore the broader impact of kinase inhibitors on breast cancer cells, SKBR3/HER2+ cells were treated with two small molecule drugs, i.e., Lapatinib (10 uM) - a Tyr kinase inhibitor, and Ipatasertib (1 uM) - a Ser/Thr kinase inhibitor. Serum-starved cells (24 h) were exposed for 36 h to Lapatinib/EGF or a combination of Lapatinib/Ipatasertib/EGF. EGF - only stimulated cells were used as control. The EGF concentration was 10 nM throughout all experiments. Proteomic profiles of nuclear and cytoplasmic cell fractions of treated vs non-treated cells were generated by nano-LC-MS/MS using an Orbitrap QE instrument.
2024-08-23 | PXD051094 | Pride
Project description:Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation foradolescent rhabdomyosarcoma (RMS) muscle cancers. Unfortunately, resistance to OT hasbeen reported in other cancers, with no counterstrategies available. Using preclinical mousexenograft experiments, we show that OT is effective at curbing RMS growth, yet a subset oftumors develop resistance that is associated with transcriptomic changes that occur in theabsence of recurrent genomic mutation. Importantly, a majority of resistant RMS modelsupregulate the PIK3CA/AKT pathway, which in turn activates NRF2 transcription factorphosphorylation and subsequent transcriptional expression of multidrug resistance ABCtransport proteins that rapidly efflux drugs from cells. We found that the PIK3CA inhibitoralpelisib re-sensitized resistant tumor cells to OT therapy by suppressing the expression of ABCtransport proteins. Excitingly, RMS use the same PIK3CA/AKT pathway activation to driveresistance to standard-of-care combination therapy vincristine, actinomycin D, andcyclophosphamide (VAC) and the combination of OT + alpelisib effectively killed VAC-resistantRMS. Alpelisib also re-sensitized resistant RMS to chemotherapy in preclinical xenograft mousemodels resulting in reduced tumor burden and extended disease-free survival. Our work definesa common resistance pathway in RMS and has credentialled a new preclinical strategy to killtherapy resistant RMS.
2025-08-08 | GSE280546 | GEO
Project description:Purpose: This study aims to identify novel targets in the rare pediatric cancer, fusion-positive rhabdomyosarcoma (FP-RMS), and examine differences/similarities in FP-RMS tumor responses to BMI1 (B lymphoma Mo-MLV insert region 1 homolog) inhibition. Methods: FP-RMS cell lines Rh28 and Rh30 were treated with DMSO (vehicle) or PTC-028, a BMI1 inhibitor, and RNA was collected after 24 or 48 hr in triplicate. RNA-seq was performed, and gene expression data were analyzed through Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses. Data from OncoPPi and the STRING database were also utilized in this study. Results: Both Rh28 and Rh30 had some overlapping pathways affected by PTC-028, notably downregulation of cell cycle progression, the DNA damage response, and cholesterol biosynthesis. Rh30+PTC-028 had more genes containing TEAD-motifs downregulated compared to Rh28+PTC-028. Rh28 and Rh30 also had differing changes in expression in kinases of LATS1/2, EPHA2, and PDGFRA. Conclusion: Overall, these results bring new insights into pathways influenced by BMI1 expression and contrasting intertumor drug responses in FP-RMS.
2021-06-11 | GSE176520 | GEO
Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy, however responses are typically short-lived1,2. Thus, there is an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as approximately 70% of TNBCs have PIK3CA/AKT1/PTEN alterations3–6. However, unlike hormone receptor-positive tumors, it is still unclear if or how PI3K pathway inhibitors will be effective in triple-negative disease7. Here we identify a promising AKT inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors potently synergize with agents that suppress the histone methyltransferase, EZH2, and promote robust tumor regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once differentiated, these agents kill TNBCs by hijacking signals that normally drive mammary gland involution. Finally, using machine learning approach, we developed a classifier that can be used for patient selection. Together these findings identify a promising therapeutic strategy for this highly aggressive tumor type and illustrate how deregulated epigenetic enzymes can insulate tumors from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.
2024-07-08 | GSE252382 | GEO