American Association for Cancer Research
21598290cd191274-sup-231409_2_table_6432467_qdl733.xlsx (229.17 kB)

Supplementary Table 7 from Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities

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posted on 2023-04-03, 22:20 authored by Marcus R. Kelly, Kaja Kostyrko, Kyuho Han, Nancie A. Mooney, Edwin E. Jeng, Kaitlyn Spees, Phuong T. Dinh, Keene L. Abbott, Dana M. Gwinn, E. Alejandro Sweet-Cordero, Michael C. Bassik, Peter K. Jackson

Results from the "Paralog" sublibrary screen. Different metrics are reported on each of the three tabs of the spreadsheet as indicated. GI-T-Score : GIT Score; MWU Adj Pval: FDR of Mann-Whitney U Test p-value after Benjamini-Hochberg correction; Double KO Phenotype : phenotype Z-score (pZ) of double knockout pair. Columns correspond to individual replicates in the indicated cell line.


National Cancer Institute


NIH Director's New Innovator Award Program

SNSF Postdoc Mobility Grants



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. 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