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A novel in vivo model of Glioblastoma radiation resistance identifies long non-coding RNAs and targetable kinases

ABSTRACT: Glioblastomas (GBM) are the most common primary CNS tumor. GBMs often recur as highly aggressive, intractable, therapy resistant tumors. Key molecular regulators of acquired radiation resistance in recurrent GBM are largely unknown with a dearth of accurate pre-clinical models. To address this, we generated eight GBM patient-derived xenograft (PDX) models of acquired radiation-therapy selected (RTS) resistance compared with same-patient, treatment naïve (RTU) PDX. A novel bioinformatics pipeline analyzed phenotypic, transcriptomic and kinomic alterations, identifying long non-coding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair (DDR) pathways in our RTS models. Multiple molecular routes to acquired radiation-resistance were revealed in our models including PDX-specific kinases that we validated with targeted small molecule inhibitors (SMIs). We identified 184, mostly novel, lncRNAs differentially regulated between RTU and RTS PDX. Several of these lncRNAs were associated with transcriptional changes in DDR, cell cycle progression, stemness, and chromatin remodeling pathways. This study identifies lncRNAs as potential key regulators in recurrent GBM and therapy resistance. We also demonstrate that SMIs aimed at lncRNA-related signaling pathways may represent a novel therapeutic approach for recurrent GBM tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206225 | GEO | 2022/07/01

REPOSITORIES: GEO

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Platinum-sensitive HGOC residual tumors share joint expression of CRYAB, CEACAM6, SOX2 genes with tumors that acquired resistance

Project description:Purpose: Most High-Grade Ovarian Carcinomas (HGOCs) are sensitive to carboplatin (CBP)-based chemotherapy but frequently recur within 24 months. Recurrent tumors remain frequently CBP-sensitive and acquire resistance after several CBP cycles. We developed Patient-Derived Xenografts (PDXs) that allow the study of these different stages of CBP-sensitive recurrence and acquisition of resistance. Experimental Design: We generated PDX models from CBP-sensitive HGOC. PDXs were CBP- or mock-treated and tumors were sampled, after treatment and at recurrence. We also isolated models with acquired-resistance from CBP-sensitive PDXs upon repeated CBP treatment. Tumors were characterized transcriptome levels by Affymetrix microarrays. Results: All PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained non-proliferating tumor cells clusters embedded in a fibrotic mesh. This was absent in CBP-resistant tumors. Residual tumors had marked differences in gene expression when compared to naïve and recurrent tumors, indicating downregulation of cell cycle and proliferation and upregulation of interferon response and epithelial–mesenchymal transition. This gene expression pattern resembled that seen in embryonal diapause and ‘drug-tolerant persister’ states. Residual and acquired-resistance tumors share the overexpression of three genes – CEACAM6, CRYAB, and SOX2. Conclusions: In HGOC PDX, CBP-sensitive recurrences arise from a small population of quiescent, drug-tolerant, residual cells embedded in a fibrotic mesh. These cells overexpress CEACAM6, CRYAB and SOX2, a signature also associated with acquired resistance and poor patient prognosis

2022-03-16 | GSE198701 | GEO

An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance

Project description:The Hippo pathway is a key growth-control pathway conserved across species. The downstream effectors of the Hippo pathway YAP/TAZ are frequently activated in cancer cells by a diverse array of mechanisms to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs are central to their transcriptional activities, we discovered a potent small molecule inhibitor (SMI) GNE-7883 that allosterically blocks the interactions between YAP/TAZ and all four TEAD paralogs in human cells through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models, and achieved strong anti-tumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes resistance to the recently approved KRAS G12C inhibitor sotorasib in both treatment-refractory and acquired resistance cell line models, providing strong proof-of-concept of TEAD SMIs in targeting YAP/TAZ-mediated KRAS inhibitor resistance. Taken together, this work demonstrates activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

2023-04-26 | GSE229071 | GEO

Homo sapiens

Project description:Gene expression profiles of PDX models with acquired resistance to endocrine treatments

| PRJNA239992 | ENA

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

2018-07-13 | GSE113816 | GEO

Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia

Project description:NOTCH1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to toxicity and development of resistance, thus restricting their clinical efficacy. Here we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta (PKCδ). We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance “in-vitro”. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

2021-03-08 | PXD018744 | Pride

G0/G1 switch gene 2 modulates gliomagenesis and radiation response

Project description:Glioblastoma multiforme (GBM), a WHO grade IV glioma is the most common and malignant primary cancer of the central nervous system with a grim median survival of 16 to 17 months upon diagnosis. Radiotherapy is the standard first line treatment for newly diagnosed patients with gliomas, but its effectiveness is limited given their intrinsic resistance and propensity for recurrence. Although possible mechanisms have been attributed to GBM resistance to radiation treatments, the molecular mechanisms regulating radiation resistance of GBM are still unclear.

2019-07-23 | GSE86213 | GEO

Expression data from OMP52M51 resistant or acute treated leukemic mice

Project description:We recently demonstrated that a human Notch1-specific neutralizing antibody (OMP52M51) was very effective in T-ALL patient derived xenografts (PDX) bearing NOTCH1/FBW7 mutations. However, we observed development of acquired resistance following long-term administration of the antibody and used PDX models to investigate this phenomenon. We analyzed expression profiles to identify genes and pathways modulated in mice treated until progression or acute treated with a neutralizing antibody against Notch1.

2020-05-20 | GSE123751 | GEO

Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair

Project description:Glioblastoma (GBM) is the most lethal brain tumour that occurs in adults and treatment for GBM has been largely unsuccessful. Ionizing radiation (IR) and chemotherapeutic agents are employed as standard of care treatment for GBM patients and both result in DNA damage. Previous data identified phosphorylation of PTEN at tyrosine 240 (pY240) in samples from patients with recurrent GBM receiving standard of care treatment and was associated with decreased overall survival. Here we demonstrate that pY240 PTEN that was triggered by FGFR2 signaling, enhanced DNA repair by facilitating the loading of PTEN onto chromatin through its interaction with KI-67 and subsequent recruitment of the DNA repair protein, RAD51, to sites of DNA damage. Thus, tumour cells with pY240 PTEN are efficient at repairing DNA damage which would be predicted to result in resistance to therapy. These findings suggest the FGFR-pY240 PTEN-DNA repair mechanism as a therapeutic target for enhancing GBM therapy.

2017-08-07 | MSV000081423 | MassIVE

Implications of the heterogeneous gene expression traits in recurrent glioblastoma

Project description:Glioblastoma multiforme (GBM) is the most aggressive and frequent primary brain tumor with dismal prognosis which might be due to the resistance to the current standard chemotherapeutic regimens and high recurrence rate even after total resection of GBM mass. Here, to gain the mechanistic insights on the altered phenotypic acquisition of recurrent tumors compared to the corresponding primary tumors, we performed gene expression profiling on the 43 cases of GBM tumors including 15 paired recurrent and primary GBMs. Unsupervised and consensus clustering analyses revealed two subtypes of G1 and G2, which were enriched with proliferation, and neuron-like gene expression traits, respectively. Most of the primary tumors were classified into G1, while the recurrent tumors were classified into both G1 and G2 groups. The gene expression of recurrent GBMs in G2 group have changed from proliferation type to neuron-like type, while the other recurrent GBMs in the G1 group showed no significant subtype change. In addition, we observed that the recurrent tumors in G1 subtype were characterized with the expression of stemness-related genes and DNA-repair genes. Of the G1 subtype classifier genes, AURKA/B and HOX genes were identified as key hub regulators. On the other hand, the recurrent G2 tumors have acquired the expression of MGMT but suppression of MSH6 gene, which may lead to TMZ resistance. The consistency of these findings could be validated with independent data sets. In summary, our molecular classification of recurrent GBMs could suggest that the differential mechanisms of drug resistance be involved in the tumor recurrence. Targeting the subtype-specific mechanisms might be a beneficial strategy for the treatment of recurrent GBMs.

2015-10-20 | GSE62153 | GEO

Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

Project description:Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.

2016-05-20 | GSE80399 | GEO

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