RT Journal Article
SR Electronic
T1 Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 563312
DO 10.1101/563312
A1 Lin, Yu-Hsiu T.
A1 Way, Gregory P.
A1 Barwick, Benjamin G.
A1 Mariano, Margarette C.
A1 Marcoulis, Makeba
A1 Ferguson, Ian D.
A1 Driessen, Christoph
A1 Boise, Lawrence H.
A1 Greene, Casey S.
A1 Wiita, Arun P.
YR 2019
UL http://biorxiv.org/content/early/2019/02/28/563312.abstract
AB 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.