{"doi":"10.1016/j.canlet.2024.217280","title":"Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis","abstract":null,"journal":"Cancer Letters","year":2024,"id":639780,"datarank":0.42402564822956657,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0643413573098109,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0643413573098109,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":9,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1662472,"name":"Bolun Jiang","orcid":null,"position":1,"is_corresponding":false},{"id":1662473,"name":"Wenchao Xu","orcid":null,"position":2,"is_corresponding":false},{"id":646853,"name":"Qiaofei Liu","orcid":"0000-0001-7148-2850","position":3,"is_corresponding":false},{"id":465162,"name":"Haoran Huang","orcid":"0000-0001-6125-5996","position":4,"is_corresponding":false},{"id":1662474,"name":"Xiaoyan Chang","orcid":null,"position":5,"is_corresponding":false},{"id":1639084,"name":"Guoxu Ma","orcid":null,"position":6,"is_corresponding":false},{"id":1202587,"name":"Xudong Xu","orcid":"0000-0002-7271-1835","position":7,"is_corresponding":false},{"id":1403010,"name":"Li Zhou","orcid":"0000-0003-3998-8725","position":8,"is_corresponding":false},{"id":1662475,"name":"Gary Guishan Xiao","orcid":null,"position":9,"is_corresponding":false},{"id":1662476,"name":"Junchao Guo","orcid":null,"position":10,"is_corresponding":false},{"id":1662469,"name":"Jianzhou Liu","orcid":"0000-0002-3721-6871","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Targeted inhibition of CHKα and mTOR in models of pancreatic ductal adenocarcinoma: A novel regimen for metastasis","abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis.","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39343354","pmcid":null,"openalex_id":"https://openalex.org/W4402910189","authors":[],"funders":[],"total_grants":0,"fwci":1.5882,"citation_percentile":0.83386598,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":6},{"year":2026,"count":3}],"oa_status":"closed","license":"https://doi.org/10.15223/policy-004","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S030438352400675X?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S030438352400675X?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.canlet.2024.217280","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39343354","host_type":"repository"}],"fields_of_study":["Phagocytosis and Immune Regulation","Epigenetics and DNA Methylation","Pancreatic and Hepatic Oncology Research","Carcinoma, Pancreatic Ductal","Humans","Animals","Pancreatic Neoplasms","Mice","TOR Serine-Threonine Kinases","Cell Line, Tumor","Choline Kinase","Xenograft Model Antitumor Assays","Cell Proliferation","Focal Adhesion Kinase 1","Checkpoint Kinase 1","Neoplasm Metastasis","Mechanistic Target of Rapamycin Complex 1","Gemcitabine","Protein Kinase Inhibitors","Deoxycytidine","Signal Transduction","Cell Movement","Hypoxia-Inducible Factor 1, alpha Subunit","Female"],"mesh_terms":["Checkpoint Kinase 1","Mechanistic Target of Rapamycin Complex 1","Gemcitabine","Animals","Cell Movement","Choline Kinase","Deoxycytidine","Female","Humans","Neoplasm Metastasis","Pancreatic Neoplasms","Signal Transduction","Carcinoma, Pancreatic Ductal","Xenograft Model Antitumor Assays","Cell Line, Tumor","Protein Kinase Inhibitors","Cell Proliferation","Mice","Focal Adhesion Kinase 1","Hypoxia-Inducible Factor 1, alpha Subunit","TOR Serine-Threonine Kinases"],"keywords":["Pancreatic ductal adenocarcinoma","PI3K/AKT/mTOR pathway","Metastasis","Cancer research","Discovery and development of mTOR inhibitors","Medicine","Regimen","Oncology","Internal medicine","Pancreatic cancer","Biology","Apoptosis","Cancer","Biochemistry","Mtor","Choline Kinase Α","Choline Kinase Inhibitor"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T01:36:00.631063Z","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":[]}