دورية أكاديمية
أعرض في EDS

Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.

التفاصيل البيبلوغرافية
العنوان: Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.
المؤلفون: Kelly MR; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California.; Program in Cancer Biology, Stanford University School of Medicine, Stanford, California., Kostyrko K; Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California., Han K; Department of Genetics, Stanford University School of Medicine, Stanford, California., Mooney NA; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California., Jeng EE; Department of Genetics, Stanford University School of Medicine, Stanford, California., Spees K; Department of Genetics, Stanford University School of Medicine, Stanford, California., Dinh PT; Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California., Abbott KL; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California., Gwinn DM; Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California., Sweet-Cordero EA; Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, California. pjackson@stanford.edu bassik@stanford.edu Alejandro.Sweet-Cordero@ucsf.edu., Bassik MC; Department of Genetics, Stanford University School of Medicine, Stanford, California. pjackson@stanford.edu bassik@stanford.edu Alejandro.Sweet-Cordero@ucsf.edu.; Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, California., Jackson PK; Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California. pjackson@stanford.edu bassik@stanford.edu Alejandro.Sweet-Cordero@ucsf.edu.; Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, California.; Department of Pathology, Stanford University School of Medicine, Stanford, California.
المصدر: Cancer discovery [Cancer Discov] 2020 Dec; Vol. 10 (12), pp. 1950-1967. Date of Electronic Publication: 2020 Jul 29.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research
مواضيع طبية MeSH: Lung Neoplasms/*genetics , Proteomics/*methods , ras Proteins/*genetics, Humans
مستخلص: Activating mutations in RAS GTPases drive many cancers, but limited understanding of less-studied RAS interactors, and of the specific roles of different RAS interactor paralogs, continues to limit target discovery. We developed a multistage discovery and screening process to systematically identify genes conferring RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry, we generated a protein-protein interaction map of RAS interactors and pathway components containing hundreds of interactions. From this network, we constructed a CRISPR dual knockout library targeting 119 RAS-related genes that we screened for KRAS -dependent genetic interactions (GI). This approach identified new RAS effectors, including the adhesion controller RADIL and the endocytosis regulator RIN1, and >250 synthetic lethal GIs, including a potent KRAS -dependent interaction between RAP1GDS1 and RHOA. Many GIs link specific paralogs within and between gene families. These findings illustrate the power of multiomic approaches to uncover synthetic lethal combinations specific for hitherto untreatable cancer genotypes. SIGNIFICANCE: We establish a deep network of protein-protein and genetic interactions in the RAS pathway. Many interactions validated here demonstrate important specificities and redundancies among paralogous RAS regulators and effectors. By comparing synthetic lethal interactions across KRAS -dependent and KRAS -independent cell lines, we identify several new combination therapy targets for RAS-driven cancers. This article is highlighted in the In This Issue feature, p. 1775 .
(©2020 American Association for Cancer Research.)
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معلومات مُعتمدة: U01 CA199216 United States CA NCI NIH HHS
المشرفين على المادة: EC 3.6.5.2 (ras Proteins)
تواريخ الأحداث: Date Created: 20200731 Date Completed: 20211124 Latest Revision: 20230331
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7710624
DOI: 10.1158/2159-8290.CD-19-1274
PMID: 32727735
قاعدة البيانات: MEDLINE
الوصف
تدمد:2159-8290
DOI:10.1158/2159-8290.CD-19-1274