title: Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models.
abstract: OBJECTIVE
  Class 1 phosphatidylinositol 3-kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here, we investigated biomarker strategies for PI3K pathway inhibitors in non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Molecular profiling for candidate PI3K predictive biomarkers was conducted on a collection of NSCLC tumor samples. Assays included comparative genomic hybridization, reverse-transcription polymerase chain reaction gene expression, mutation detection for PIK3CA and other oncogenes, PTEN immunohistochemistry, and FISH for PIK3CA copy number. In addition, a panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers.
  
  
  RESULTS
  PIK3CA amplification was detected in 37% of squamous tumors and 5% of adenocarcinomas, whereas PIK3CA mutations were found in 9% of squamous and 0% of adenocarcinomas. Total loss of PTEN immunostaining was found in 21% of squamous tumors and 4% of adenocarcinomas. Cell lines harboring pathway alterations (receptor tyrosine kinase activation, PI3K mutation or amplification, and PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a mitogen-activated protein-extracellular signal-regulated kinase inhibitor had greater effects on cell viability than PI3K inhibition alone.
  
  
  CONCLUSIONS
  Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with nonsquamous NSCLC patient populations.
authors.affiliation: Departments of Oncology Biomarker Development, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Spoerke
authors.forename: Carol
authors.initials: C
authors.lastname: O'Brien
authors.forename: Ling
authors.initials: L
authors.lastname: Huw
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Jane
authors.initials: J
authors.lastname: Fridlyand
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Brachmann
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Ajay
authors.initials: A
authors.lastname: Pandita
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Leanne
authors.initials: L
authors.lastname: Ross
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019086:Bridged Bicyclo Compounds, Heterocyclic; D058534:Class I Phosphatidylinositol 3-Kinases; D000069347:Erlotinib Hydrochloride; D007191:Indazoles; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C484760:PIK3CA protein, human; C494929:PTEN protein, human