A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-X L Anti-apoptotic Protein in Kidney Cancer
A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-X L Anti-apoptotic Protein in Kidney Cancer
Abstract Genome-wide genetic screens have identified cellular dependencies in many cancers. Using the Broad Institute’s Achilles shRNA screening dataset, we mined for targetable dependencies by cell lineage. Our studies identified a strong dependency on BCL2L1, which encodes the BCL-XL anti-apoptotic protein, in a subset of kidney cancer cells. Genetic and pharmacological inactivation of BCL-XL, but not the related anti-apoptotic proteins BCL-2, led to fitness defects in renal cancer cells, and also sensitized them to chemotherapeutics. Neither BCL-XL levels (absolute or normalized to BCL-2) nor the status of the VHL gene, which is frequently mutated in kidney cancer, predicted BCL-XL dependence. Transcriptional profiling, however, identified a ‘BCL-XL dependency’ mRNA signature, which included elevated mesenchymal gene expression in BCL-XL dependent cells. Promoting mesenchymal transition increased BCL-XL dependence; whereas, conversion to a more differentiated state overcame BCL-XL dependence in kidney cancer cells. The ‘BCL-XL dependency’ mRNA signature was observed in almost a third of human clear cell Renal Cell Carcinomas (ccRCCs), which were also associated with worse clinical outcomes. Finally, an orally bioavailable BCL-XL inhibitor, A-1331852, showed anti-tumor efficacy in vivo. Altogether, our studies uncovered an unexpected link between cancer cell state and dependence on the anti-apoptotic BCL-XL protein and justify further testing on BCL-XL blockade as a potential way to target a clinically aggressive subset of human kidney cancers. One Sentence SummaryCell state, but not pVHL and/or HIF status, defines the dependency of kidney cancer cells on the BCL-XL anti-apoptotic protein.
Krill-Burger John Michael、Vazquez Francisca、Grubb Treg、Radivoyevitch Tomas、Sarosiek Kristopher A.、Stransky Laura、Chakraborty Abhishek A.、Maganti Smruthi、Kaelin William G. Jr.、Fraser Cameron
Broad Institute of Harvard and MITBroad Institute of Harvard and MITDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic||Case Comprehensive Cancer Center, Case Western Reserve UniversityQuantitative Health Sciences, Lerner Research Institute, Cleveland ClinicJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health||Department of Environmental Health, Harvard T.H. Chan School of Public HealthDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women?ˉs Hospital, Harvard Medical SchoolDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic||Case Comprehensive Cancer Center, Case Western Reserve UniversityDepartment of Cancer Biology, Lerner Research Institute, Cleveland Clinic||Case Comprehensive Cancer Center, Case Western Reserve UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women?ˉs Hospital, Harvard Medical School||Howard Hughes Medical InstituteJohn B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health||Department of Environmental Health, Harvard T.H. Chan School of Public Health
肿瘤学基础医学分子生物学
Krill-Burger John Michael,Vazquez Francisca,Grubb Treg,Radivoyevitch Tomas,Sarosiek Kristopher A.,Stransky Laura,Chakraborty Abhishek A.,Maganti Smruthi,Kaelin William G. Jr.,Fraser Cameron.A Mesenchymal Tumor Cell State Confers Increased Dependency on the BCL-X L Anti-apoptotic Protein in Kidney Cancer[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2022.01.29.478337.点此复制
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