Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma
| Autor: | Frances A. Tosto, Ping Chen, Dickran Kazandjian, Craig J. Thomas, George E. Wright, Kelli M. Wilson, Thomas Oellerich, James W. Lord, Carleen Klumpp-Thomas, Irina Maric, Grace Smith, Crystal McKnight, Da-Wei Huang, Jan Wisnieski, Xin Yu, Ryan M. Young, Björn Häupl, Michele Ceribelli, Arnold Bolomsky, James Q. Wang, Erin S Beck, Callie K. Van Winkle, Jameson Travers, James D. Phelan, Stefania Pittaluga, Yandan Yang |
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| Rok vydání: | 2022 |
| Předmět: |
Gene isoform
chemistry.chemical_classification MAPK/ERK pathway Mitogen-Activated Protein Kinase Kinases Multidisciplinary Chemistry Mutant General Physics and Astronomy mTORC1 General Chemistry Mechanistic Target of Rapamycin Complex 1 General Biochemistry Genetics and Molecular Biology Amino acid Genes ras Mutation Cancer research Humans Protein Isoforms Amino acid transporter Amino Acids Multiple Myeloma Gene PI3K/AKT/mTOR pathway Transcription Factors |
| Zdroj: | Nature communications. 13(1) |
| ISSN: | 2041-1723 |
| Popis: | Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling. |
| Databáze: | OpenAIRE |
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