title: Identification of a subset of human non-small cell lung cancer patients with high PI3Kβ and low PTEN expression, more prevalent in squamous cell carcinoma.
abstract: OBJECTIVE
  The phosphoinositide 3-kinase (PI3K) pathway is a major oncogenic signaling pathway and an attractive target for therapeutic intervention. Signaling through the PI3K pathway is moderated by the tumor suppressor PTEN, which is deficient or mutated in many human cancers. Molecular characterization of the PI3K signaling network has not been well defined in lung cancer; in particular, the role of PI3Kβ and its relation to PTEN in non-small cell lung cancer NSCLC remain unclear.
  
  
  METHODS
  Antibodies directed against PI3Kβ and PTEN were validated and used to examine, by immunohistochemistry, expression in 240 NSCLC resection tissues [tissue microarray (TMA) set 1]. Preliminary observations were extended to an independent set of tissues (TMA set 2) comprising 820 NSCLC patient samples analyzed in a separate laboratory applying the same validated antibodies and staining protocols. The staining intensities for PI3Kβ and PTEN were explored and colocalization of these markers in individual tumor cores were correlated.
  
  
  RESULTS
  PI3Kβ expression was elevated significantly in squamous cell carcinomas (SCC) compared with adenocarcinomas. In contrast, PTEN loss was greater in SCC than in adenocarcinoma. Detailed correlative analyses of individual patient samples revealed a significantly greater proportion of SCC in TMA set 1 with higher PI3Kβ and lower PTEN expression when compared with adenocarcinoma. These findings were reinforced following independent analyses of TMA set 2.
  
  
  CONCLUSIONS
  We identify for the first time a subset of NSCLC more prevalent in SCC, with elevated expression of PI3Kβ accompanied by a reduction/loss of PTEN, for whom selective PI3Kβ inhibitors may be predicted to achieve greater clinical benefit.
authors.affiliation: Authors' Affiliations: AstraZeneca R&D; Former AstraZeneca, Macclesfield, Cheshire, United Kingdom; Departments of Translational Molecular Pathology and Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; AstraZeneca, Asia and Emerging Markets iMed, Shanghai, China; Novartis Institutes for BioMedical Research, Basel, Switzerland; and Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
authors.forename: Marie
authors.initials: M
authors.lastname: Cumberbatch
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.forename: Garry
authors.initials: G
authors.lastname: Beran
authors.forename: Sonia
authors.initials: S
authors.lastname: Eckersley
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Rebecca P A
authors.initials: RP
authors.lastname: Ellston
authors.forename: Simon
authors.initials: S
authors.lastname: Dearden
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.forename: Shuqiong
authors.initials: S
authors.lastname: Fan
authors.forename: Neil
authors.initials: N
authors.lastname: Gray
authors.forename: David P
authors.initials: DP
authors.lastname: Blowers
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Chris
authors.initials: C
authors.lastname: Womack
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D046888:Tissue Array Analysis
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human