title: Target Identification in Small Cell Lung Cancer via Integrated Phenotypic Screening and Activity-Based Protein Profiling.
abstract: To overcome hurdles in identifying key kinases in small cell lung cancer (SCLC), we integrated a target-agnostic phenotypic screen of kinase inhibitors with target identification using activity-based protein profiling (ABPP) in which a desthiobiotin-ATP probe was used. We screened 21 SCLC cell lines with known c-MYC amplification status for alterations in viability using a chemical library of 235 small-molecule kinase inhibitors. One screen hit compound was interrogated with ABPP, and, through this approach, we reidentified Aurora kinase B as a critical kinase in MYC-amplified SCLC cells. We next extended the platform to a second compound that had activity in SCLC cell lines lacking c-MYC amplification and identified TANK-binding kinase 1, a kinase that affects cell viability, polo-like kinase-1 signaling, G2-M arrest, and apoptosis in SCLC cells lacking MYC amplification. These results demonstrate that phenotypic screening combined with ABPP can identify key disease drivers, suggesting that this approach, which combines new chemical probes and disease cell screens, has the potential to identify other important targets in other cancer types. Mol Cancer Ther; 15(2); 334-42. ©2016 AACR.
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Jiannong
authors.initials: J
authors.lastname: Li
authors.affiliation: Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Fumi
authors.initials: F
authors.lastname: Kinose
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Yian A
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: John M
authors.initials: JM
authors.lastname: Koomen
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. eric.haura@moffitt.org.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000302:isolation & purification* / Q000378:metabolism; D001710:Biotin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; C489427:MYC protein, human; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D054852:Small Molecule Libraries; D001710:Biotin; C004749:desthiobiotin