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

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. Winkle, Xin Yu, Jan Wisniewski, James Q. Wang, Frances A. Tosto, Erin Beck, Kelli Wilson, Crystal McKnight, Jameson Travers, Carleen Klumpp-Thomas, Grace A. Smith, Stefania Pittaluga, Irina Maric, Dickran Kazandjian, Craig J. Thomas and Ryan M. Young ()
Additional contact information
Yandan Yang: National Cancer Institute, National Institutes of Health
Arnold Bolomsky: National Cancer Institute, National Institutes of Health
Thomas Oellerich: Goethe University
Ping Chen: National Cancer Institute, National Institutes of Health
Michele Ceribelli: National Institutes of Health
Björn Häupl: Goethe University
George W. Wright: National Cancer Institute, National Institutes of Health
James D. Phelan: National Cancer Institute, National Institutes of Health
Da Wei Huang: National Cancer Institute, National Institutes of Health
James W. Lord: National Cancer Institute, National Institutes of Health
Callie K. Winkle: National Cancer Institute, National Institutes of Health
Xin Yu: National Cancer Institute, National Institutes of Health
Jan Wisniewski: National Cancer Institute, National Institutes of Health
James Q. Wang: National Cancer Institute, National Institutes of Health
Frances A. Tosto: National Institutes of Health
Erin Beck: National Institutes of Health
Kelli Wilson: National Institutes of Health
Crystal McKnight: National Institutes of Health
Jameson Travers: National Institutes of Health
Carleen Klumpp-Thomas: National Institutes of Health
Grace A. Smith: National Cancer Institute, National Institutes of Health
Stefania Pittaluga: National Cancer Institute, National Institutes of Health
Irina Maric: National Institutes of Health Clinical Center
Dickran Kazandjian: University of Miami Health System
Craig J. Thomas: National Cancer Institute, National Institutes of Health
Ryan M. Young: National Cancer Institute, National Institutes of Health

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33142-x

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