Suppressing Aberrant Hedgehog Pathway and Overcoming Resistance to Smoothened Antagonists via Targeting Super-enhancer-driven Transcriptional Dependencies
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE266391 | GEO | 2024/05/16
REPOSITORIES: GEO
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Project description:Aberrant activation of Hedgehog (Hh) signaling pathway plays important roles in both oncogenesis and targeted therapy of many cancers. The clinical application of FDA-approved Hh-targeted Smoothened inhibitor (SMOi) drugs is hindered due to the emergence of various primary or acquired drug resistance, indicating the need of novel anti-Hh therapies. Our previous studies demonstrate that epigenetic/transcriptional targeted therapies represent a promising direction for anti-Hh drug development. In this study, we identified CDK9 and CDK12, two transcription elongation regulators, as novel therapeutic targets for antagonizing the aberrant Hh pathway and overcoming SMOi resistance. CDK9 inhibition and CDK12 inhibition exhibited similarly potent anti-Hh activities when treating various SMOi responsive or resistant Hh-driven tumor models as previously reported BET inhibition or CDK7 inhibition. We also utilized SHH-subtype medulloblastoma (SHH-MB) as the representative Hh-driven cancer model to perform Super-enhancer (SE) analysis and elucidate the crucial roles of SE in Hh-driven oncogenesis and above-mentioned anti-Hh epigenetic/transcriptional targeted therapies. Furthermore, we identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target of multiple Hh-driven tumor models, including the SMOi-resistant ones. Collectively, our study demonstrates that the SE-driven transcriptional dependencies represent promising therapeutic vulnerabilities for suppressing the aberrant Hh pathway and overcoming the SMOi resistance. As CDK9 inhibitor and IRS inhibitor drugs have already entered human clinical trials for cancer treatment, our study provides comprehensive preclinical support for expanding their trials to Hh-driven cancers in near future.
2024-05-16 | GSE266386 | GEO
Project description:Aberrant activation of Hedgehog (Hh) signaling pathway plays important roles in both oncogenesis and targeted therapy of many cancers. The clinical application of FDA-approved Hh-targeted Smoothened inhibitor (SMOi) drugs is hindered due to the emergence of various primary or acquired drug resistance, indicating the need of novel anti-Hh therapies. Our previous studies demonstrate that epigenetic/transcriptional targeted therapies represent a promising direction for anti-Hh drug development. In this study, we identified CDK9 and CDK12, two transcription elongation regulators, as novel therapeutic targets for antagonizing the aberrant Hh pathway and overcoming SMOi resistance. CDK9 inhibition and CDK12 inhibition exhibited similarly potent anti-Hh activities when treating various SMOi responsive or resistant Hh-driven tumor models as previously reported BET inhibition or CDK7 inhibition. We also utilized SHH-subtype medulloblastoma (SHH-MB) as the representative Hh-driven cancer model to perform Super-enhancer (SE) analysis and elucidate the crucial roles of SE in Hh-driven oncogenesis and above-mentioned anti-Hh epigenetic/transcriptional targeted therapies. Furthermore, we identified IRS1, encoding a critical component and cytoplasmic adaptor protein of the IGF pathway, as an oncogenic Hh-driven SE target gene and effective therapeutic target of multiple Hh-driven tumor models, including the SMOi-resistant ones. Collectively, our study demonstrates that the SE-driven transcriptional dependencies represent promising therapeutic vulnerabilities for suppressing the aberrant Hh pathway and overcoming the SMOi resistance. As CDK9 inhibitor and IRS inhibitor drugs have already entered human clinical trials for cancer treatment, our study provides comprehensive preclinical support for expanding their trials to Hh-driven cancers in near future.
2024-05-16 | GSE266389 | 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:The G protein-coupled receptor (GPCR) smoothened (SMO) is a key signaling component of the sonic hedgehog (Hh) pathway and a clinically validated target for cancer treatment. The FDA-approved SMO inhibitors GDC-0449/Vismodegib and LDE225/Sonidegib demonstrated clinical antitumor efficacy. Nevertheless, relatively high percentage of treated patients would eventually develop acquired cross resistance to both drugs. Here, based on published structure and activity of GDC-0449 inhibitor class, we replaced its amide core with benzimidazole which retained bulk of the SMO-targeting activity as measured in our Hh/SMO/Gli1-reporter system. Synthesis and screening of multiple series of benzimidazole derivatives identified HH-1, HH-13, and HH-20 with potent target suppression (IC50: <0.1??mol/L) in the reporter assays. In NIH3T3 cells stimulated with a secreted Hh (SHH), these inhibitors dose dependently reduced mRNA and protein expression of the endogenous pathway components PTCH-1, Gli1, and cyclin D1 resulting in growth inhibition via G0/G1 arrest. Mechanistically, the SMO-targeted growth inhibition involved downregulation of mTOR signaling inputs and readouts consistent with diminished mTORC1/mTORC2 functions and apoptosis. In mice, as with GDC-0449, orally administered HH inhibitors blocked paracrine activation of stromal Hh pathway in Calu-6 tumor microenvironment and attenuated growth of PTCH+/-/P53-/- medulloblastoma allograft tumors. Furthermore, HH-13 and HH-20 potently targeted the drug-resistant smoothened SMO-D473H (IC50: <0.2??mol/L) compared to the poor inhibition by GDC-0449 (IC50: >60??mol/L). These results identify HH-13 and HH-20 as potent inhibitors capable of targeting naïve and drug-resistant Hh/SMO-driven cancers. The current leads may be optimized to improve pharmaceutical property for potential development of new therapy for treatment of Hh pathway-driven cancers.
| S-EPMC6329794 | biostudies-literature
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: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: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:Hedgehog (Hh) signaling promotes tumorigenesis. The accumulation of the membrane protein Smoothened (Smo) within the primary cilium (PC) is a key event in Hh signal transduction, and many pharmacological inhibitors identified to date target Smo's actions. Smo ciliary translocation is inhibited by some pathway antagonists, while others promote ciliary accumulation, an outcome that can lead to a hypersensitive state on renewal of Hh signaling. To identify novel inhibitory compounds acting on the critical mechanistic transition of Smo accumulation, we established a high content screen to directly analyze Smo ciliary translocation. Screening thousands of compounds from annotated libraries of approved drugs and other agents, we identified several new classes of compounds that block Sonic hedgehog-driven Smo localization within the PC. Selective analysis was conducted on two classes of Smo antagonists. One of these, DY131, appears to inhibit Smo signaling through a common binding site shared by previously reported Smo agonists and antagonists. Antagonism by this class of compound is competed by high doses of Smo-binding agonists such as SAG and impaired by a mutation that generates a ligand-independent, oncogenic form of Smo (SmoM2). In contrast, a second antagonist of Smo accumulation within the PC, SMANT, was less sensitive to SAG-mediated competition and inhibited SmoM2 at concentrations similar to those that inhibit wild-type Smo. Our observations identify important differences among Hh antagonists and the potential for development of novel therapeutic approaches against mutant forms of Smo that are resistant to current therapeutic strategies.
| S-EPMC3905677 | biostudies-literature
Project description:Targeting Hedgehog pathway by Smoothened Antagonist
| PRJNA720577 | ENA