title: Navitoclax enhances the efficacy of taxanes in non-small cell lung cancer models.
abstract: OBJECTIVE
  To explore the potential of navitoclax in combination with taxane-based chemotherapy in the treatment of non-small cell lung cancer (NSCLC) by defining mechanism of synergy and identifying correlative biomarkers.
  
  
  METHODS
  We treated a panel of NSCLC lines with a dose matrix of paclitaxel and navitoclax (formerly ABT-263), an inhibitor of Bcl-2, Bcl-x(L), and Bcl-w (1), and evaluated synergy. We next used time-lapse microscopy to explore mechanism of synergy. Finally, we developed an immunohistochemical assay and assessed prevalence of Bcl-x(L) in NSCLC tumor tissues.
  
  
  RESULTS
  All cell lines exhibit greater than additive response to the combination of navitoclax and a taxane. These results were extended to mouse xenograft tumor models, in which the combination is more efficacious than either single-agent docetaxel or navitoclax. Addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-x(L) and Mcl-1 correlate with the extent of synergy, suggesting that cancers with elevated levels of Bcl-x(L) will be relatively resistant to taxane-based therapy but could benefit from the addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit relatively high Bcl-x(L) levels.
  
  
  CONCLUSIONS
  The addition of navitoclax to taxane-based chemotherapy in NSCLC has the potential to increase efficacy, particularly in patients whose tumors express high levels of Bcl-x(L).
authors.affiliation: Department of Research Oncology, Bio-informatics, and Protein Engineering, Genentech Inc, South San Francisco, California 94080, USA.
authors.forename: Nguyen
authors.initials: N
authors.lastname: Tan
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Malek
authors.forename: Jiping
authors.initials: J
authors.lastname: Zha
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Robert
authors.initials: R
authors.lastname: Kassees
authors.forename: Leanne
authors.initials: L
authors.lastname: Berry
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D018929:Cell Culture Techniques; D002453:Cell Cycle; D019070:Cell Lineage; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008938:Mitosis; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000737:chemistry*; D013997:Time Factors; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D013449:Sulfonamides; D043823:Taxoids; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins; D017239:Paclitaxel; C528561:navitoclax