The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma
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PROVIDER: PRJNA1179367 | ENA |
REPOSITORIES: ENA
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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:Hypertrophic scar (HS) is a skin fibroproliferative disease currently having no truly effective therapy. PIK3CA is a catalytic subunit of PI3K able to promote collagen synthesis in benign fibrotic diseases and to regulate cell survival, proliferation, and adhesion in malignancies. To explore PIK3CA’s functions in HS formation, we performed transcriptome sequencing and experimental validation. PIK3CA were overexpressed in HS tissues, and positively correlated with fibrosis. We then screened out miR-203a-3p as the most suitable endogenous inhibitor of PIK3CA through bioinformatics. Intriguingly, miR-203a-3p suppressed the proliferation, migration, collagen synthesis, and contractility, as well as trans-differentiation of fibroblasts into myofibroblasts in vitro, improved the morphology and histology of HS in vivo. Mechanistically, miR-203a-3p attenuated fibrosis by inactivating PI3K/AKT/mTOR pathway via directly targeting PIK3CA. In conclusion, Our findings identified that PIK3CA and PI3K/AKT/mTOR pathway were actively involved in HS formation and demonstrated that miR-203a-3p might serve as a potential strategy for HS therapy through targeting PIK3CA and inactivating PI3K/AKT/mTOR pathway.
2023-07-15 | GSE236983 | GEO
Project description:Activation of the epithelial-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers (CRCs) contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with CRC contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine Specific Demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer (CRC) and enhances cell migration. In this study we determine that LSD1 expression is significantly elevated in CRC patients with mutation of the catalytic subunit of PI3K, PIK3CA, compared to CRC patients with WT PIK3CA. LSD1 enhances activation of the AKT kinase in CRC cells through a non-catalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. Additionally, growth of PIK3CA mutant CRC cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of PIK3CA mutant cells.
2019-11-06 | GSE139925 | GEO
Project description:Activation of the epithelial-mesenchymal transition (EMT) program is a critical mechanism for initiating cancer progression and migration. Colorectal cancers (CRCs) contain many genetic and epigenetic alterations that can contribute to EMT. Mutations activating the PI3K/AKT signaling pathway are observed in >40% of patients with CRC contributing to increased invasion and metastasis. Little is known about how oncogenic signaling pathways such as PI3K/AKT synergize with chromatin modifiers to activate the EMT program. Lysine Specific Demethylase 1 (LSD1) is a chromatin-modifying enzyme that is overexpressed in colorectal cancer (CRC) and enhances cell migration. In this study we determine that LSD1 expression is significantly elevated in CRC patients with mutation of the catalytic subunit of PI3K, PIK3CA, compared to CRC patients with WT PIK3CA. LSD1 enhances activation of the AKT kinase in CRC cells through a non-catalytic mechanism, acting as a scaffolding protein for the transcription-repressing CoREST complex. Additionally, growth of PIK3CA mutant CRC cells is uniquely dependent on LSD1. Knockdown or CRISPR knockout of LSD1 blocks AKT-mediated stabilization of the EMT-promoting transcription factor Snail and effectively blocks AKT-mediated EMT and migration. Overall we uniquely demonstrate that LSD1 mediates AKT activation in response to growth factors and oxidative stress, and LSD1-regulated AKT activity promotes EMT-like characteristics in a subset of PIK3CA mutant cells.
2019-11-06 | GSE139924 | GEO
Project description:LSD1 mediates AKT activity in PIK3CA mutant colorectal cancer
| PRJNA587634 | ENA
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:Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. More-over, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. We used microarrays to detail the global programme of gene expression after transduction of AKT and RAS IMR90 cells were transfected with Control, AKT and RAS retrovirus containing medium in 4 replicates. Fibroblasts were drug selected and kept in drug for duration of experiments.
2013-03-19 | E-GEOD-45276 | biostudies-arrayexpress
Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:Miswired enhancer logic drives translocation positive rhabdomyosarcoma
| PRJNA563682 | ENA
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.
2015-08-13 | E-GEOD-71981 | biostudies-arrayexpress