{"doi":"10.1101/2022.02.03.479021","title":"Therapeutic vulnerability to ATR inhibition in concurrent <i>NF1</i> and <i>ATRX-</i> deficient high-grade solid tumors","abstract":"Abstract Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and presence of alternative lengthening of telomeres (ALT). In addition, a potential biologic vulnerability of ALT-positive cancer cells is ATR inhibition, a regulator of homologous recombination. We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. For these experiments, cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), a NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), a NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors (AZD6738 and VE-822), in vitro, with or without a MEK inhibitor (AZD6244, selumetinib) or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition (AZD6738 and VE-822) in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition (AZD6244), irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line (ATRX loss/ALT-positive) demonstrated sensitivity to ATR inhibition (AZD6738), but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in the MPNST cell line ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors. Tumors with pre-existing ALT, or that subsequently develop ALT after ATRX downregulation, are particularly vulnerable to this therapeutic approach.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299781,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232275,"name":"Charles G. Eberhart","orcid":"0000-0002-2910-9427","position":1,"is_corresponding":false},{"id":80024,"name":"Christine A. Pratilas","orcid":"0000-0002-7116-0605","position":2,"is_corresponding":false},{"id":80025,"name":"Jaishri O. Blakeley","orcid":"0000-0002-1049-0993","position":3,"is_corresponding":false},{"id":632131,"name":"Christine Davis","orcid":"0000-0002-5022-2838","position":4,"is_corresponding":false},{"id":932310,"name":"Marija Stojanova","orcid":null,"position":5,"is_corresponding":false},{"id":85402,"name":"Karlyne M. Reilly","orcid":"0000-0001-9109-4409","position":6,"is_corresponding":false},{"id":278996,"name":"Alan K. Meeker","orcid":"0000-0003-4601-6481","position":7,"is_corresponding":false},{"id":404994,"name":"Christopher M. Heaphy","orcid":"0000-0003-4264-1810","position":8,"is_corresponding":false},{"id":288108,"name":"Fausto J. Rodríguez","orcid":"0000-0001-8662-1219","position":9,"is_corresponding":false},{"id":844385,"name":"Ming Yuan","orcid":"0000-0003-4940-8253","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T00:31:49.412501Z","pmid":null,"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":[]}