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

Author

Listed:
  • 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
    National Institutes of Health)

  • Ryan M. Young

    (National Cancer Institute, National Institutes of Health)

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.

Suggested Citation

  • 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 Wis, 2022. "Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33142-x
    DOI: 10.1038/s41467-022-33142-x
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    1. Arthur L. Shaffer & N. C. Tolga Emre & Laurence Lamy & Vu N. Ngo & George Wright & Wenming Xiao & John Powell & Sandeep Dave & Xin Yu & Hong Zhao & Yuxin Zeng & Bangzheng Chen & Joshua Epstein & Louis, 2008. "IRF4 addiction in multiple myeloma," Nature, Nature, vol. 454(7201), pages 226-231, July.
    2. Michael A. Chapman & Michael S. Lawrence & Jonathan J. Keats & Kristian Cibulskis & Carrie Sougnez & Anna C. Schinzel & Christina L. Harview & Jean-Philippe Brunet & Gregory J. Ahmann & Mazhar Adli & , 2011. "Initial genome sequencing and analysis of multiple myeloma," Nature, Nature, vol. 471(7339), pages 467-472, March.
    3. Seweryn Mroczek & Justyna Chlebowska & Tomasz M. Kuliński & Olga Gewartowska & Jakub Gruchota & Dominik Cysewski & Vladyslava Liudkovska & Ewa Borsuk & Dominika Nowis & Andrzej Dziembowski, 2017. "The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    4. Kendall R. Sanson & Ruth E. Hanna & Mudra Hegde & Katherine F. Donovan & Christine Strand & Meagan E. Sullender & Emma W. Vaimberg & Amy Goodale & David E. Root & Federica Piccioni & John G. Doench, 2018. "Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    5. Ian D. Ferguson & Bonell Patiño-Escobar & Sami T. Tuomivaara & Yu-Hsiu T. Lin & Matthew A. Nix & Kevin K. Leung & Corynn Kasap & Emilio Ramos & Wilson Nieves Vasquez & Alexis Talbot & Martina Hale & A, 2022. "The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Douglas E. Biancur & Joao A. Paulo & Beata Małachowska & Maria Quiles Del Rey & Cristovão M. Sousa & Xiaoxu Wang & Albert S. W. Sohn & Gerald C. Chu & Steven P. Gygi & J. Wade Harper & Wojciech Fendle, 2017. "Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    7. James D. Phelan & Ryan M. Young & Daniel E. Webster & Sandrine Roulland & George W. Wright & Monica Kasbekar & Arthur L. Shaffer & Michele Ceribelli & James Q. Wang & Roland Schmitz & Masao Nakagawa &, 2018. "A multiprotein supercomplex controlling oncogenic signalling in lymphoma," Nature, Nature, vol. 560(7718), pages 387-391, August.
    8. Ruth Milkereit & Avinash Persaud & Liviu Vanoaica & Adriano Guetg & Francois Verrey & Daniela Rotin, 2015. "LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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