Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE164311 | GEO | 2021/01/06
REPOSITORIES: GEO
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Project description:Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models
| PRJNA689834 | ENA
Project description:Study of mouse medulloblastoma in response to inhibitor of Smoothened. Keywords: gene modification
2008-03-01 | GSE7212 | GEO
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:Study of mouse medulloblastoma in response to inhibitor of Smoothened. Experiment Overall Design: Several signal array comparisons are used to supplement other forms of data. There are insufficent replicates for a statistical treatment.
2008-04-06 | E-GEOD-7212 | biostudies-arrayexpress
Project description:Aberrant activation of Hedgehog pathway is responsible for initiation and maintenance of various cancers, including medulloblastoma (MB), basal cell carcinoma (BCC), and other solid and hematological tumors. Therefore, targeting Hh pathway represents promising therapeutic prospects for Hh-driven cancers. In recent years, tremendous efforts have been dedicated to the discovery of Hh pathway inhibitor. While the majority of Hh pathway inhibitors target the upstream membrane protein Smoothened (SMO). Here, we performed Next Generation Sequencing to reveal the target genes of Hh pathway by treating mouse SHH-subtype medulloblastoma cells (SmoWT) with SMO inhibitor (GDC0449) or DMSO.
2021-07-08 | GSE171689 | GEO
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:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis. We previously generated a SmoA1 transgenic mouse medulloblastoma model, which expresses the SmoA1 transgene driven by the GNP-specific fragment of the promoter of ND2 transcription factor leading to constitutively active Shh signaling exclusively in the cerebellum. In this study, we characterize the ND2:SmoA2 transgenic mouse model with a similarly designed transgene expressing the SmoA2 mutation. To assess transcriptional changes downstream of SmoA1 and SmoA2, we evaluated global gene expression profiles of P5 SmoA1, SmoA2 and Wt age-matched cerebella. We chose this specific developmental stage because (1) the phenotypes of SmoA1 and SmoA2 are robust and distinct at P5; (2) at P5 GNPs undergo proliferation, migration and differentiation and therefore expression profiling could capture key differences in multiple processes.
2012-11-02 | E-GEOD-34593 | biostudies-arrayexpress
Project description:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis.
2012-11-02 | GSE34593 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
2022-02-16 | PXD023137 | Pride
Project description:Cdk4 and Cdk6 are two related kinases that bind D-type cyclins and regulate cell cycle progression. Due to their relevance in cancer, Cdk4/6 inhibitors are currently in advanced clinical trials in multiple tumor types. Cdk4/6 are inhibited by INK4 proteins that exert tumor suppressing functions. To test the significance of this inhibitory mechanism we have generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6R/R mice display altered development of the hematopoietic system without resulting in enhanced tumor susceptibility, either in the presence or absence of p53. The presence of the Cdk6 R31C allele results in defective potential of hematopoietic progenitors in adoptive transfer assays or after induced damage. These defects are rescued after complete insensitivity to INK4 inhibitors in Cdk4R/R; Cdk6R/R double mutant mice, and INK4-resistant mice display increased susceptibility to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, the presence of the Cdk6 R31C allele results in increased binding of p16INK4a to wild-type Cdk4, whereas the double mutant is fully insensitive to INK4 inhibitors resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in tumor development and suggest a role for Cdk6 in buffering INK4 protein levels thus contributing to the development of hematopoietic tumors. The presence of the Cdk4 R24C and Cdk6 R31C alleles results in relevant changes in the expression profiles of cancer cells including deregulation of apoptosis and other processes. p185BCR-ABL1 was used to transform wild-type or double knock-in Cdk4 R24C; Cdk6 R31C fetal livers. Cell lines were isolated as spontaneous immortal and transformed clones after transduction of fetal liver with a p185 BCR-ABL1-transgene. RNA was isolated from asynchronous cultures. Two-condition experiment, Cdk4R-Cdk6R cells versus wild-type cells. Biological replicates: 3 control replicates, 3 transfected replicates.
2014-11-04 | E-GEOD-59024 | biostudies-arrayexpress