ArticleThe Journal of clinical investigation2021
Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- Ubiquitin-dependent degradation of p27Kip1 and p21Waf1/Cip1 by AMBRA1 ensures G1 and S phase progression and limits replication stress.Nucleic acids research · 2026Article
- FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy.Cancer research · 2026Article
- Reprogramming lipid metabolism in pediatric cancers.Oncogenesis · 2026Review
- Bone marrow-derived mesenchymal stem cell ameliorates post-stroke enterobacterial translocation through liver-gut axis.Stroke and vascular neurology · 2025Article
- Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies.Cancers · 2024Review
- Single-cell transcriptomic analysis identifies downregulated phosphodiesterase 8B as a novel oncogene in IDH-mutant glioma.Frontiers in immunology · 2024Article
- Evolving Diagnostic and Treatment Strategies for Pediatric CNS Tumors: The Impact of Lipid Metabolism.Biomedicines · 2023Review
- Research progress in molecular pathology markers in medulloblastoma.Exploration of targeted anti-tumor therapy · 2023Review
- The opportunities and challenges for nutritional intervention in childhood cancers.Frontiers in nutrition · 2023Review
- Cholesterol in the ciliary membrane as a therapeutic target against cancer.Frontiers in molecular biosciences · 2023Review
- Genome-wide CRISPR/Cas9 screening for drug resistance in tumors.Frontiers in pharmacology · 2023Review
- Sterol regulation of developmental and oncogenic Hedgehog signaling.Biochemical pharmacology · 2022Review
- Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib.Science advances · 2022Article
- Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma.Frontiers in cell and developmental biology · 2022Review
- CDK 4/6 inhibitors for the treatment of meningioma.Frontiers in oncology · 2022Review
- Review
- Targeting PI3K, FGFR, CDK4/6 Signaling Pathways Together With Cytostatics and Radiotherapy in Two Medulloblastoma Cell Lines.Frontiers in oncology · 2021Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Medulloblastoma is an aggressive pediatric brain tumor that can be driven by misactivation of the Hedgehog (HH) pathway. CDK6 is a critical effector of oncogenic HH signaling, but attempts to target the HH pathway in medulloblastoma have been encumbered by resistance to single-agent molecular therapy. We identified mechanisms of resistance to CDK6 inhibition in HH-associated medulloblastoma by performing orthogonal CRISPR and CRISPR interference screens in medulloblastoma cells treated with a CDK4/6 inhibitor and RNA-Seq of a mouse model of HH-associated medulloblastoma with genetic deletion of Cdk6. Our concordant in vitro and in vivo data revealed that decreased ribosomal protein expression underlies resistance to CDK6 inhibition in HH-associated medulloblastoma, leading to ER stress and activation of the unfolded protein response (UPR). These pathways increased the activity of enzymes producing Smoothened-activating (SMO-activating) sterol lipids that sustained oncogenic HH signaling in medulloblastoma despite cell-cycle attenuation. We consistently demonstrated that concurrent genetic deletion or pharmacological inhibition of CDK6 and HSD11ß2, an enzyme producing SMO-activating lipids, additively blocked cancer growth in multiple mouse genetic models of HH-associated medulloblastoma. Our data reveal what we believe to be a novel pathway of resistance to CDK4/6 inhibition as well as a novel combination therapy to treat the most common malignant brain tumor in children.
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