{"doi":"10.1172/jci141171","title":"Smoothened-activating lipids drive resistance to CDK4/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models","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.","journal":"Journal of Clinical Investigation","year":2021,"id":171397,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":706877,"name":"Jordan Hochstelter","orcid":null,"position":1,"is_corresponding":false},{"id":706878,"name":"Anirudh Bommireddy","orcid":null,"position":2,"is_corresponding":false},{"id":267241,"name":"Abrar Choudhury","orcid":"0000-0001-8312-2457","position":3,"is_corresponding":false},{"id":571213,"name":"Alexis Leigh Krup","orcid":"0000-0001-5555-0155","position":4,"is_corresponding":false},{"id":706879,"name":"Pervinder Kaur","orcid":null,"position":5,"is_corresponding":false},{"id":507748,"name":"Pakteema Tong","orcid":null,"position":6,"is_corresponding":false},{"id":493839,"name":"Amy Li","orcid":"0000-0002-7732-3540","position":7,"is_corresponding":false},{"id":334296,"name":"Libin Xu","orcid":"0000-0003-1021-5200","position":8,"is_corresponding":false},{"id":74141,"name":"Jeremy F. Reiter","orcid":"0000-0002-6512-320X","position":9,"is_corresponding":false},{"id":88538,"name":"David R. Raleigh","orcid":"0000-0001-9299-8864","position":10,"is_corresponding":false},{"id":426692,"name":"Vikas Daggubati","orcid":"0000-0002-9779-4614","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:46:33.067299Z","pmid":"33476305","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}