title: Reinforcing targeted therapeutics with phenotypic stability factors.
abstract: Deregulated cell cycle progression can often be traced to intrinsic defects in specific regulatory proteins in cancer cells. Knowledge of these primary defects has led to targeted approaches that exploit the defects and spare normal cells. However, the success of such targeted approaches is still hit-or-miss. Genetic and epigenetic variability inherent in most tumors often results in phenotypic heterogeneity that, in turn, results in de novo or acquired resistance to therapeutic agents. The ability of cells to compensate and adapt to the inhibition of a specific cell cycle mediator is not remarkable. What is novel and of great potential importance is that the ability of cells to exhibit such adaptability varies markedly. "Phenotypic stability factors" that restrict the ability of cells to undergo epithelial-mesenchymal transitions (EMT) may dictate the success or failure of targeted therapies by interfering with compensatory changes such as deregulation of CDK2 activity. Identification of existing and new agents that induce and maintain phenotypic stability factors will inform and enable synergistic approaches to the eradication of even the most aggressive tumors.
authors.affiliation: a Life Sciences Division ; Lawrence Berkeley National Laboratory ; Berkeley , CA USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Yaswen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C475820:CCNE1 protein, human; D056741:Cyclin D; D019927:Cyclin E; D016328:NF-kappa B; D015513:Oncogene Proteins; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: CDK, cyclin-dependent kinase; CSC, cancer stem cell; EMT, epithelial-mesenchymal transition; ER, estrogen receptor; GSI, γ-secretase inhibitor; HER2, Human Epidermal Growth Factor Receptor 2; NF-κB; NICD, Notch intracellular domain; Notch; Ovol; TGFβ; cancer therapy; cyclin-dependent kinase (CDK); drug resistance; epithelial-mesenchymal transition (EMT); inflammation