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

James Q Wang, Ryan M Young, Craig J Thomas, Dickran Kazandjian, Irina Maric, Stefania Pittaluga, Grace A Smith, Carleen Klumpp-Thomas, Jameson Travers, Crystal McKnight, Kelli Wilson, Erin Beck, Frances A Tosto, Yandan Yang, Jan Wisniewski, Xin Yu, Callie K Van Winkle, James W Lord, Da Wei Huang, James D Phelan, George W Wright, Björn Häupl, Michele Ceribelli, Ping Chen, Thomas Oellerich, Arnold Bolomsky

Journal: Nature communications 2022;13(1):5469

PMID: 36115844

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Abstract

Oncogenic RAS mutations 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 employ an unbiased proteogenomic approach to dissect RAS signaling in MM. We discover that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes are more aggressive and enriched in RAS mutations, and we detect interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergizes 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 mode of RAS signaling.

Address: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.; Department of Medicine II, Heamatology/Oncology, Goethe University, 60323, Frankfurt, Germany.; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.; Biometric Research Branch, DCTD, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.; Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.; Hematology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, 20892, USA.; Department of Medicine, University of Miami Health System, Miami, FL, 33136, USA.; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected].

DOI: 10.1038/s41467-022-33142-x