title: Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization.
abstract: Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs. We observed that lapatinib-induced acquired resistance in SUM149 cells led to cross-resistance to other targeted- and chemotherapeutic drugs. Removal of the primary drug to which the model was developed led to re-sensitization to multiple drugs to a degree comparable to the parental cell line; this coincided with the cells regaining the ability to accumulate ROS and reduced expression of anti-apoptotic factors and the antioxidant SOD2. We suggest that our findings provide a unique IBC model system for gaining an understanding of acquired therapeutic resistance and the effect of redox adaptation on anti-cancer drug efficacy.
authors.affiliation: Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, USA. kpwilliams@nccu.edu
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Williams
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Allensworth
authors.forename: Shalonda M
authors.initials: SM
authors.lastname: Ingram
authors.forename: Ginger R
authors.initials: GR
authors.lastname: Smith
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Aldrich
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Sexton
authors.forename: Gayathri R
authors.initials: GR
authors.lastname: Devi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy*; D000077341:Lapatinib; D011799:Quinazolines / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077341:Lapatinib
keywords: Lapatinib; Redox adaptation; SUM149; SUM190; XIAP; qHTS