Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

• DOI: 10.1038/s41467-022-33142-x
• Publication Date: 2022-09-17T11:05:40Z
• Authors: Yandan Yang; Arnold Bolomsky; Thomas Oellerich; Ping Chen; Michele Ceribelli; Björn Häupl; George W. Wright; James D. Phelan; Da Wei Huang; James W. Lord; Callie K. Van Winkle; Xin Yu; Jan Wisniewski; James Q. Wang; Frances A. Tosto; Erin Beck; Kelli Wilson; Crystal McKnight; Jameson Travers; Carleen Klumpp-Th...; Grace A. Smith; Stefania Pittaluga; Irina Maric; Dickran Kazandjian; Craig J. Thomas; Ryan M. Young
• Keywords: Mitogen-Activated Protein Kinase Kinases; Genes, ras; Science; Q; Mutation; Humans; Protein Isoforms; Amino Acids; Mechanistic Target of Rapamycin Complex 1; Multiple Myeloma; Article; Transcription Factors

Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms pathogenic signaling this disease remain enigmatic and difficult to inhibit therapeutically. We employ unbiased proteogenomic approach dissect MM. discover that mutant isoforms organize a complex with amino acid transporter, SLC3A2, MTOR on endolysosomes, which directly activates mTORC1 by co-opting sensing pathways. MM tumors high expression mTORC1-dependent genes more aggressive enriched mutations, we detect interactions between patient harboring isoforms. Inhibition RAS-dependent activity synergizes MEK ERK inhibitors quench This study redefines pathway provides mechanistic rational basis target mode signaling.