Abstract 4172: Identification of a low PTEN / high PI3Kα expressing subset of squamous non-small-cell lung cancer (NSCLC)
Authors: Garry Beran, Xi M. Tang, Marie Cumberbatch, Sally Luke, Pritibha Singh, Alexander Kvist, Sabina Cosulich, Paul D. Smith, Carmen Behrens, Edward S. Kim, Chris Womack, Neil Gray, Ignacio I. Wistuba, David P. Blowers
Journal: Cancer Research (2012)

Abstract Background The PI3K/AKT/mTOR signalling network is a critical regulator of many cellular processes including proliferation, survival and transformation. PI3Kα and PI3Kα are positioned on chromosome 3q (3q25-27), a region often amplified in NSCLC. The activity of the PI3K enzymes is counteracted by the tumor suppressor PTEN, a nonredundant phosphatase. Clinically, PTEN mutations and deficiencies are prevalent in many types of human cancers and severe PTEN deficiency is also associated with advanced tumor stage and therapeutic resistance. In lung cancer, loss of PTEN protein occurs via a number of mechanisms including promoter methylation and LOH, however, neither epigenetic silencing nor deletion appear to predict with protein loss by immunohistochemistry (IHC). The molecular characterization of the PI3K/AKT/mTOR signalling network in lung cancer is not as well defined as in other tumour types, yet de-regulation of this pathway has been linked to resistance to therapy (EGFR). In particular, the role of PI3Kα in NSCLC has not been studied. Methods Eight tissue microarrays (TMAs) comprising 211 surgically resected formalin-fixed paraffin-embedded NSCLC specimens (99 squamous cell carcinomas; 112 adenocarcinomas) were examined by IHC using validated antibodies directed against PI3Kα and PTEN. In addition, an independent investigation was conducted at the MDACC using the same validated antibody methods across thirty two TMAs comprising 290 squamous and 530 adenocarcinoma samples. Results Tumour expression of PI3Kα was largely cytoplasmic, while PTEN was localized to both cytoplasmic and nuclear compartments. Results from the AZ dataset reveal significantly (p&amp;lt;0.001) elevated expression of cytoplasmic PI3Kα expression in squamous cell carcinomas compared with adenocarcinomas. Conversely, adenocarcinoma samples displayed significantly higher levels of cytoplasmic (p&amp;lt;0.001) and nuclear (p&amp;lt;0.001) PTEN (88.3% and 74.8% positive, respectively) compared with squamous samples (60.6% and 45.5% positive, respectively). Interestingly, over-expression of cytoplasmic PI3Kα in squamous samples correlated significantly (66.3% of squamous samples; p&amp;lt;0.001) with negative or low cytoplasmic and nuclear PTEN expression, with only 11.5% of adenocarcinoma samples showing this pattern of expression and 50% exhibiting a converse relationship. Analyses of data derived from the MDACC identified a similar profile of expression confirming identification of a subset of squamous NSCLC samples with over-expression of PI3Kα and low or negative PTEN. Supplementary evaluation of KRAS and EGFR mutation status and survival endpoints in this segment has also been performed and will be discussed. Conclusions These data identify a pattern of over-expression of PI3Kα in squamous NSCLC that, accompanied by loss/reduced PTEN, could represent a subset for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4172. doi:1538-7445.AM2012-4172