title: Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets.
abstract: In prostate cancer, multiple metastases from the same patient share similar copy number, mutational status, erythroblast transformation specific (ETS) rearrangements, and methylation patterns supporting their clonal origins. Whether actionable targets such as tyrosine kinases are also similarly expressed and activated in anatomically distinct metastatic lesions of the same patient is not known. We evaluated active kinases using phosphotyrosine peptide enrichment and quantitative mass spectrometry to identify druggable targets in metastatic castration-resistant prostate cancer obtained at rapid autopsy. We identified distinct phosphopeptide patterns in metastatic tissues compared with treatment-naive primary prostate tissue and prostate cancer cell line-derived xenografts. Evaluation of metastatic castration-resistant prostate cancer samples for tyrosine phosphorylation and upstream kinase targets revealed SRC, epidermal growth factor receptor (EGFR), rearranged during transfection (RET), anaplastic lymphoma kinase (ALK), and MAPK1/3 and other activities while exhibiting intrapatient similarity and interpatient heterogeneity. Phosphoproteomic analyses and identification of kinase activation states in metastatic castration-resistant prostate cancer patients have allowed for the prioritization of kinases for further clinical evaluation.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, Division of Hematology and Oncology, Department of Medicine, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Institute for Molecular Medicine, California NanoSystems Institute, and Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Drake
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Graham
authors.forename: John K
authors.initials: JK
authors.lastname: Lee
authors.forename: Tanya
authors.initials: T
authors.lastname: Stoyanova
authors.forename: Claire M
authors.initials: CM
authors.lastname: Faltermeier
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.forename: Björn
authors.initials: B
authors.lastname: Titz
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods*; D025341:Principal Component Analysis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000201:enzymology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D019000:Phosphotyrosine; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases
keywords: combination therapy; metastasis; personalized medicine; phosphotyrosine; resistance