title: Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer.
abstract: OBJECTIVE
  To investigate the combination of conventional cytotoxic anticancer agents and a small molecule kinase inhibitor in preclinical models of non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  We compared the induction of apoptosis by DNA-damaging anticancer drugs and PKC412, a predominantly protein kinase C (PKC)-specific small molecule inhibitor, in six NSCLC cell lines of different histologic and genetic backgrounds. The outcome of various combinations and schedules of DNA-damaging agents and PKC412 was studied, and isobolograms were calculated. Conditional expression of pro-apoptotic BAK was applied to specifically target apoptotic signal transduction in combination with drug therapy.
  
  
  RESULTS
  Resistance of NSCLC cells to DNA damage-induced apoptosis was mainly determined at the mitochondrial step of the intrinsic pathway of caspase activation. PKC412 effectively inhibited the growth factor signal transduction, but failed to induce apoptosis in NSCLC cells resistant to DNA-damaging agents. Combining conventional anticancer drugs with PKC412 at different doses and schedules resulted in unpredictable outcomes, including synergistic, additive, and antagonistic interactions. In contrast, conditional expression of BAK reliably sensitized drug-resistant NSCLC cells to apoptosis induced by cytotoxic agents or PKC412.
  
  
  CONCLUSIONS
  Combining DNA-damaging anticancer drugs with a pharmacologic inhibitor of growth and survival factor signaling in NSCLC may result in unpredictable treatment outcomes. In contrast, targeting specific death effector mechanisms, such as apoptotic signal transduction, is a promising strategy to sensitize NSCLC to cytotoxic agents or kinase inhibitors.
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Meiler
authors.forename: Melanie
authors.initials: M
authors.lastname: Guyot
authors.forename: Sandra
authors.initials: S
authors.lastname: Hoffarth
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Wesarg
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Höhn
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004336:Drug Antagonism; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003609:Dactinomycin; D005047:Etoposide; D004317:Doxorubicin; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin; D017239:Paclitaxel