We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.
Bibliographical noteFunding Information:
We thank members of the O.N.W. and J.M.S. labs for helpful comments and discussion on the manuscript and the University of Michigan for supplying material from their rapid autopsy program. J.M.D. is supported by the Department of Defense Prostate Cancer Research Program W81XWH-14-1-0148 , Prostate Cancer Foundation Young Investigator Award , and a New Jersey Health Foundation Research grant . N.A.G. is supported by UCLA Scholars in Oncologic Molecular Imaging (SOMI) program, NIH grant R25T CA098010 . J.K.L. is supported by Specialty Training and Advanced Research (STAR) Program at UCLA , Prostate Cancer Foundation Young Investigator Award , and Tower Cancer Research Foundation Career Development Award . B.A.S. is supported by the UCLA Tumor Immunology Training grant T32 CA009120 , American Cancer Society Postdoctoral Fellowship PF-16-082-01-TBE , and Prostate Cancer Foundation Young Investigator Award . T.S. is supported by Prostate Cancer Foundation Young Investigator Award and NIH / National Cancer Institute K99 Pathway to Independence Award 4R00CA184397 . C.M.F. is supported by the UCLA Medical Scientist Training Program . J.H. is supported by NIH grants 5R01CA172603-02 , 2P30CA016042-39 , 1R01CA181242-01A1 , 1R01CA195505 , the Department of Defense Prostate Cancer Research Program W81XWH-12-1-0206 , UCLA SPORE in prostate cancer , Prostate Cancer Foundation Honorable A. David Mazzone Special Challenge Award , and UCLA Jonsson Comprehensive Cancer Center Impact Grant . J.A.W. is supported by NIH GM089778 . T.G.G. is supported by the NCI / NIH P01 CA168585 , an American Cancer Society Research Scholar Award RSG-12-257-01-TBE , the CalTech-UCLA Joint Center for Translational Medicine , the UCLA Jonsson Cancer Center Foundation , the National Center for Advancing Translational Sciences UCLA CTSI grant UL1TR000124 , and a Concern Foundation CONquer CanCER Now Award . J.M.S. is supported by NCI / NIH U24-CA143858 , NCI / NIH 1R01CA180778 , NHGRI / NIH 5U54HG006097 , and NIGMS / NIH 5R01GM109031 grants. O.N.W. is an Investigator of the Howard Hughes Medical Institute and is supported by the Zimmerman Family , the Concern Foundation , and by a Prostate Cancer Foundation Challenge Award . J.H., T.G.G., J.M.S., and O.N.W. are supported by the West Coast Prostate Cancer Dream Team supported by Stand Up to Cancer / AACR / Prostate Cancer Foundation SU2C-AACR-DT0812 (O.N.W. co-PI). This research grant is made possible by the generous support of the Movember Foundation . Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.