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Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma

View ORCID ProfileYu-Hsiu T. Lin, View ORCID ProfileGregory P. Way, View ORCID ProfileBenjamin G. Barwick, Margarette C. Mariano, Makeba Marcoulis, View ORCID ProfileIan D. Ferguson, Christoph Driessen, Lawrence H. Boise, View ORCID ProfileCasey S. Greene, View ORCID ProfileArun P. Wiita
doi: https://doi.org/10.1101/563312
Yu-Hsiu T. Lin
1Department of Laboratory Medicine, University of California, San Francisco, CA 94107, USA
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Gregory P. Way
2Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
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Benjamin G. Barwick
3Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA, 30332, USA
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Margarette C. Mariano
1Department of Laboratory Medicine, University of California, San Francisco, CA 94107, USA
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Makeba Marcoulis
1Department of Laboratory Medicine, University of California, San Francisco, CA 94107, USA
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Ian D. Ferguson
1Department of Laboratory Medicine, University of California, San Francisco, CA 94107, USA
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Christoph Driessen
4Experimental Oncology and Hematology, Dept. of Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland
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Lawrence H. Boise
3Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA, 30332, USA
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Casey S. Greene
2Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
5Childhood Cancer Data Lab, Alex’s Lemonade Stand Foundation, Philadelphia, PA 19102, USA
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Arun P. Wiita
1Department of Laboratory Medicine, University of California, San Francisco, CA 94107, USA
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  • For correspondence: Arun.wiita@ucsf.edu
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ABSTRACT

A major driver of multiple myeloma is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employ an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in multiple myeloma to inform precision medicine strategies. Collectively, these predictive models identify vulnerable signaling signatures and highlight surprising differences in functional signaling patterns between NRAS and KRAS mutants invisible to the genomic landscape. Transcriptional analysis suggests that aberrant MAPK pathway activation is only present in a fraction of RAS-mutated vs. WT RAS patients. These high-MAPK patients, enriched for NRAS Q61 mutations, have inferior outcomes whereas RAS mutations overall carry no survival impact. We further develop an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. These results may lead to improved stratification of MM patients in clinical trials while also revealing unexplored modes of Ras biology.

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Posted February 28, 2019.
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Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma
Yu-Hsiu T. Lin, Gregory P. Way, Benjamin G. Barwick, Margarette C. Mariano, Makeba Marcoulis, Ian D. Ferguson, Christoph Driessen, Lawrence H. Boise, Casey S. Greene, Arun P. Wiita
bioRxiv 563312; doi: https://doi.org/10.1101/563312
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Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma
Yu-Hsiu T. Lin, Gregory P. Way, Benjamin G. Barwick, Margarette C. Mariano, Makeba Marcoulis, Ian D. Ferguson, Christoph Driessen, Lawrence H. Boise, Casey S. Greene, Arun P. Wiita
bioRxiv 563312; doi: https://doi.org/10.1101/563312

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