title: BYL719, a selective inhibitor of phosphoinositide 3-Kinase α, enhances the effect of selumetinib (AZD6244, ARRY-142886) in KRAS-mutant non-small cell lung cancer.
abstract: OBJECTIVE
  KRAS is frequently mutated in non-small cell lung cancers (NSCLC), resulting in activation of the MEK/ERK pathway. Because there are currently no drugs that target oncogenic KRAS, MEK inhibitors have been tested clinically as a possible treatment option for patients with NSCLC. However, KRAS-mutant cancers exhibit resistance to MEK inhibitors. Therefore, a combinational strategy is necessary for effective therapy. To address this, we investigated the therapeutic effects of combining selumetinib, a MEK1/2 inhibitor, with BYL719, a PI3Kα inhibitor.
  
  
  METHODS
  We evaluated the effects of selumetinib and BYL719 in vitro and in vivo in NSCLC cell lines.
  
  
  RESULTS
  The combination of BYL719 and selumetinib resulted in synergistic cytotoxic activity compared with the single agents alone in KRAS-mutant NSCLC cells. At the molecular level, we found that AKT activation strongly influenced the sensitivity of KRAS-mutant NSCLC cells to selumetinib. Selumetinib upregulated phospho-AKT and phosphorylated BAD at ser136, which is responsible for intrinsic drug resistance in KRAS-mutant NSCLC cells. In contrast, inhibition of the PI3K/AKT pathway by BYL719 hindered selumetinib-induced BAD phosphorylation and increased the antitumor efficacy of selumetinib. Furthermore, selumetinib and BYL719 combination therapy showed synergy in the suppression of A549 xenograft tumor growth. On analysis of the pharmacodynamics, selumetinib and BYL719 together resulted in effective inhibition of both p-ERK and p-AKT expression in tumor tissue.
  
  
  CONCLUSIONS
  Taken together, these data suggest that combination treatment with selumetinib and BYL719 is a promising therapeutic approach to overcoming resistance to MEK inhibitors.
authors.affiliation: Samsung Biomedical Research Institute, Seoul, South Korea.
authors.forename: Bo Mi
authors.initials: BM
authors.lastname: Ku
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Jho
authors.forename: Yeon-Hee
authors.initials: YH
authors.lastname: Bae
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Ahn
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008807:Mice, Inbred BALB C; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013844:Thiazoles / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D013844:Thiazoles; C585539:Alpelisib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins