title: Protein pathway activation mapping of brain metastasis from lung and breast cancers reveals organ type specific drug target activation.
abstract: Brain metastases are the most common fatal complication of systemic cancer, especially of lung (40-50%) and breast (20-30%) cancers. In this era of personalized therapy, there is a critical need to uncover the signaling architecture of brain metastases; however, little is known about what signaling pathways are activated in the context of the brain microenvironment. Using a unique study set of 42 brain metastases from patients with breast or nonsmall cell lung cancer (NSCLC), the phosphorylation/activation states of 128 key signaling proteins involved in cancer signaling were measured in laser capture microdissected tumor epithelium using reverse phase protein microarray (RPMA) technology. Distinct pathway activation subgroups from both breast and lung metastases were underpinned by, among others, ERBB2, AKT, mTOR, EGFR, SMAD, and ERK-p38 signaling. Breast cancer metastases showed significantly (p < 0.05) higher activation of the c-ERBB2/IGFR-AKT pathway network compared to NSCLC metastases, whereas NSCLC metastases to the brain exhibited higher relative levels of many members of the EGFR-ERK signaling network. Protein pathway activation mapping using RPMA revealed both the heterogeneity of signaling networks in brain metastases that would require a prior stratification to targeted therapies as well as the requirement of direct analysis of the metastatic lesion.
authors.affiliation: I.R.C.C.S. Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Improta
authors.forename: Angela
authors.initials: A
authors.lastname: Zupa
authors.forename: Helen
authors.initials: H
authors.lastname: Fillmore
authors.forename: Jianghong
authors.initials: J
authors.lastname: Deng
authors.forename: Michele
authors.initials: M
authors.lastname: Aieta
authors.forename: Pellegrino
authors.initials: P
authors.lastname: Musto
authors.forename: Lance A
authors.initials: LA
authors.lastname: Liotta
authors.forename: William
authors.initials: W
authors.lastname: Broaddus
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: Julia D
authors.initials: JD
authors.lastname: Wulfkuhle
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007834:Lasers; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways; D042282:Microdissection; D058990:Molecular Targeted Therapy; D009928:Organ Specificity; D010766:Phosphorylation; D057285:Precision Medicine; D040081:Protein Array Analysis / Q000379:methods*; D025941:Protein Interaction Mapping / Q000379:methods*; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor