PMID- 31698452 OWN - NLM STAT- MEDLINE DCOM- 20200901 LR - 20200901 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 3 IP - 21 DP - 2019 Nov 12 TI - Integrated phosphoproteomics and transcriptional classifiers reveal hidden RAS signaling dynamics in multiple myeloma. PG - 3214-3227 LID - 10.1182/bloodadvances.2019000303 [doi] AB - A major driver of multiple myeloma (MM) is thought to be aberrant signaling, yet no kinase inhibitors have proven successful in the clinic. Here, we employed an integrated, systems approach combining phosphoproteomic and transcriptome analysis to dissect cellular signaling in MM to inform precision medicine strategies. Unbiased phosphoproteomics initially revealed differential activation of kinases across MM cell lines and that sensitivity to mammalian target of rapamycin (mTOR) inhibition may be particularly dependent on mTOR kinase baseline activity. We further noted differential activity of immediate downstream effectors of Ras as a function of cell line genotype. We extended these observations to patient transcriptome data in the Multiple Myeloma Research Foundation CoMMpass study. A machine-learning-based classifier identified surprisingly divergent transcriptional outputs between NRAS- and KRAS-mutated tumors. Genetic dependency and gene expression analysis revealed mutated Ras as a selective vulnerability, but not other MAPK pathway genes. Transcriptional analysis further suggested that aberrant MAPK pathway activation is only present in a fraction of RAS-mutated vs wild-type RAS patients. These high-MAPK patients, enriched for NRAS Q61 mutations, have inferior outcomes, whereas RAS mutations overall carry no survival impact. We further developed an interactive software tool to relate pharmacologic and genetic kinase dependencies in myeloma. 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. These results will lead to improved stratification of MM patients in precision medicine trials while also revealing unexplored modes of Ras biology in MM. CI - (c) 2019 by The American Society of Hematology. FAU - Lin, Yu-Hsiu T AU - Lin YT AD - Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA. FAU - Way, Gregory P AU - Way GP AD - Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA. FAU - Barwick, Benjamin G AU - Barwick BG AD - Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA. FAU - Mariano, Margarette C AU - Mariano MC AD - Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA. FAU - Marcoulis, Makeba AU - Marcoulis M AD - Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA. FAU - Ferguson, Ian D AU - Ferguson ID AD - Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA. FAU - Driessen, Christoph AU - Driessen C AD - Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland; and. FAU - Boise, Lawrence H AU - Boise LH AD - Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA. FAU - Greene, Casey S AU - Greene CS AD - Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA. AD - Childhood Cancer Data Laboratory, Alex's Lemonade Stand Foundation, Philadelphia, PA. FAU - Wiita, Arun P AU - Wiita AP AD - Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA. LA - eng GR - DP2 GM123500/GM/NIGMS NIH HHS/United States GR - P30 CA138292/CA/NCI NIH HHS/United States GR - T32 HG000046/HG/NHGRI NIH HHS/United States GR - R01 CA226851/CA/NCI NIH HHS/United States GR - K08 CA184116/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Phosphoproteins) RN - 0 (Protein Kinase Inhibitors) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Computational Biology/methods MH - Female MH - *Gene Expression Profiling MH - Humans MH - MAP Kinase Signaling System MH - Machine Learning MH - Male MH - Molecular Sequence Annotation MH - Multiple Myeloma/drug therapy/*genetics/*metabolism/pathology MH - Mutation MH - Phosphoproteins/*metabolism MH - Precision Medicine/methods MH - Protein Kinase Inhibitors/pharmacology MH - *Proteomics/methods MH - *Signal Transduction/drug effects MH - *Transcriptome MH - ras Proteins/genetics/metabolism PMC - PMC6855123 COIS- Conflict-of-interest disclosure: A.P.W. has received past research funding from TeneoBio, Sutro BioPharma, and Quadriga BioSciences and is a member of the scientific advisory board and equity holder of Indapta Therapeutics and Protocol Intelligence. The remaining authors declare no competing financial interests. EDAT- 2019/11/08 06:00 MHDA- 2020/09/02 06:00 PMCR- 2019/10/29 CRDT- 2019/11/08 06:00 PHST- 2019/04/15 00:00 [received] PHST- 2019/08/23 00:00 [accepted] PHST- 2019/11/08 06:00 [entrez] PHST- 2019/11/08 06:00 [pubmed] PHST- 2020/09/02 06:00 [medline] PHST- 2019/10/29 00:00 [pmc-release] AID - 422647 [pii] AID - 2019/ADV2019000303 [pii] AID - 10.1182/bloodadvances.2019000303 [doi] PST - ppublish SO - Blood Adv. 2019 Nov 12;3(21):3214-3227. doi: 10.1182/bloodadvances.2019000303.