title: Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.
abstract: The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Schwartz
authors.forename: Brad
authors.initials: B
authors.lastname: Scroggins
authors.forename: Abbey
authors.initials: A
authors.lastname: Zuehlke
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kijima
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Alok
authors.initials: A
authors.lastname: Mishra
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Thomas
authors.initials: T
authors.lastname: Prince
mesh_terms: D000818:Animals; D023281:Genomics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases