Targeting resistance to Smoothened antagonists by inhibiting the PI3K pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE22007 | GEO | 2010/09/29
SECONDARY ACCESSION(S): PRJNA127469
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE22005: Medulloblastoma tumors derived from Ptch+/-HIC+/- transgenic mouse allografted in nude mice GSE22006: Medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse allografted in nude mice Refer to individual Series
2010-09-29 | E-GEOD-22007 | biostudies-arrayexpress
Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. mRNA profiling: RNA was prepared from tumours from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Affymetrix Mouse Genome 430 2.0 RNA expression array. The dosage terminology (BID & QD) reflects the dosing schedule, where BID = twice a day, QD = once a day. aCGH: DNA was prepared from tumors from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Agilent mouse CGH 244K Array.
2010-09-29 | E-GEOD-19657 | biostudies-arrayexpress
Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma.
2010-09-29 | GSE19657 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-16 | GSE266391 | GEO
Project description:The malignant brain cancer medulloblastoma is characterized by mutations in Hedgehog (Hh) signaling pathway genes, which lead to constitutive activation of the G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor Smoothened (Smo). The Smo antagonist NVP-LDE225 inhibits Hh signaling and induces tumor regression in animal models of medulloblastoma. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed several resistance mechanisms. We noted chromosomal amplification of Gli2, a downstream effector of Hh signaling, and, more rarely, point mutations in Smo that led to reactivated Hh signaling and restored tumor growth. Analysis of pathway gene expression signatures also, unexpectedly, identified up-regulation of phosphatidylinositol 3-kinase (PI3K) signaling in resistant tumors as another potential mechanism of resistance. Probing the relevance of increased PI3K signaling, we demonstrated that addition of the PI3K inhibitor NVP-BKM120 or the dual PI3K-mTOR (mammalian target of rapamycin) inhibitor NVP-BEZ235 to the initial treatment with the Smo antagonist markedly delayed the development of resistance. Our findings may be useful in informing treatment strategies for medulloblastoma.
| S-EPMC3422576 | biostudies-literature
Project description:Resistance to clinically available targeted drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies have demonstrated two epigenetic/transcriptional targeted therapeutic strategies, BET inhibition and CDK7 inhibition, could overcome both primary and acquired resistance to Smoothened inhibitor (SMOi) drugs, providing a promising direction for novel anti-hedgehog drug development. In this study, we performed CRISPR-Cas9 screening of epigenetic/transcriptional targeted sgRNA library in hedgehog-driven medulloblastoma (SHH-MB) cells and combined with tumor dataset analyses to identify other potential epigenetic/transcriptional targeted strategies for treating aberrant hedgehog pathway and overcoming SMOi-resistance. Our results demonstrated structure specific recognition protein 1 (SSRP1), a subunit of Facilitates Chromatin Transcription (FACT) complex, was a hedgehog-induced essential oncogene and therapeutic target of hedgehog-driven cancer. FACT inhibitor CBL0137, which has entered human clinical trials against cancer, could effectively suppress multiple mouse and human hedgehog-driven cancer models that are either SMOi-responsive or -resistant both in vitro and in vivo. Mechanistically, CBL0137 exerted its anti-hedgehog activity mainly through targeting the transcription of GLI1/2, which are core transcription factors of hedgehog pathway. ChIP-qPCR analyses further revealed SSRP1 could bind to the promoter regions of GLI1/2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 could work synergistically with BET inhibitor or CDK7 inhibitor on antagonizing aberrant hedgehog pathway and growth of either SMOi-responsive or -resistant hedgehog-driven cancer models. Taken together, our study identified FACT inhibition as another promising epigenetic/transcriptional targeted therapeutic strategy for treating hedgehog-driven cancer and overcoming SMOi-resistance.
2021-07-08 | GSE171685 | GEO
Project description:The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all so-far described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.
| S-EPMC6600918 | biostudies-literature
Project description:Targeting resistance to Smoothened antagonists by FACT inhibition
| PRJNA720568 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-05-15 | E-GEOD-53270 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-01-01 | E-GEOD-45970 | biostudies-arrayexpress