title: AKT inhibition synergistically enhances growth-inhibitory effects of gefitinib and increases apoptosis in non-small cell lung cancer cell lines.
abstract: OBJECTIVE
  EGFR inhibitors are ineffective against most EGFR wild-type non-small cell lung cancer, for which novel treatment strategies are needed. AKT signalling is essential for mediating EGFR survival signals in NSCLC. We evaluated the combination of gefitinib and two different AKT inhibitors, the allosteric inhibitor AKTi-1/2 and the ATP-competitive pan-AKT inhibitor AZD5363, in EGFR-mutant (HCC-827 and PC-9) and -wild-type (NCI-H522, NCI-H1651), non-small cell lung cancer cell lines.
  
  
  METHODS
  Drug interaction was studied in two EGFR mutant and two EGFR wild-type non-small cell lung cancer cell lines by calculating combination index (CI) using median effect analysis. The effects on p-EGFR, p-ERK, p-AKT, p-S6 and apoptosis were studied by Western blot analysis.
  
  
  RESULTS
  The combination of gefitinib and AKTi-1/2 or AZD5363 showed synergistic growth inhibition in all cell lines. CI values for the combination of gefitinib and AKTi-1/2 were 0.35 (p=0.0048), 0.56 (p=0.036), 0.75 (p=0.13) and 0.64 (p=0.0003) in NCI-H522, NCI-H1651, HCC-827 and PC-9 cell lines, respectively; CI values of 0.45 (p=0.0087) and 0.22 (p<0.0001) were observed in NCI-H522 and PC-9 cells, respectively, when gefitinib was combined with AZD5363. Additive inhibition of signalling output through AKT and key downstream proteins (S6) and increased apoptosis were demonstrated.
  
  
  CONCLUSIONS
  Dual inhibition of EGFR and AKT may be a useful up-front strategy for patients with EGFR-mutant and -wild-type non-small cell lung cancer.
authors: The Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, London, UK; The Lung Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors: M
authors: M
authors: Puglisi
authors: The Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, London, UK.
authors: P
authors: P
authors: Thavasu
authors: The Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, London, UK.
authors: A
authors: A
authors: Stewart
authors: The Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, London, UK.
authors: J S
authors: JS
authors: de Bono
authors: The Lung Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors: M E R
authors: ME
authors: O'Brien
authors: The Lung Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors: S
authors: S
authors: Popat
authors: The Lung Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors: J
authors: J
authors: Bhosle
authors: The Drug Development Unit, Divisions of Cancer Therapeutics & Clinical Studies, The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: udai.banerji@icr.ac.uk.
authors: U
authors: U
authors: Banerji
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
keywords: AKT; Akt inhibitor; EGFR; Gefitinib; NSCLC; S6; Synergism