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Identification of a subset of human non-small cell lung cancer patients with high PI3Kbeta and low PTEN expression, more prevalent in squamous cell carcinoma

Cumberbatch, M and Tang, X and Beran, G and Eckersley, S and Wang, X and Ellston, RPA and Dearden, S and Cosulich, S and Smith, PD and Behrens, C and Kim, ES and Su, X and Fan, S and Gray, N and Blowers, DP and Wistuba, II and Womack, C (2014) Identification of a subset of human non-small cell lung cancer patients with high PI3Kbeta and low PTEN expression, more prevalent in squamous cell carcinoma. Clinical Cancer Research. pp. 595-603.

Abstract

Purpose: 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 PI3Kbeta and its relation to PTEN in non-small cell lung cancer NSCLC remain unclear. Experimental Design: Antibodies directed against PI3Kbeta 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 820NSCLC patient samples analyzed in a separate laboratory applying the same validated antibodies and staining protocols. The staining intensities for PI3Kbeta and PTEN were explored and colocalization of these markers in individual tumor cores were correlated. Results: PI3Kbeta 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 PI3Kbeta 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 PI3Kbeta accompanied by a reduction/loss of PTEN, for whom selective PI3Kbeta inhibitors may be predicted to achieve greater clinical benefit. 2014 American Association for Cancer Research

Item Type: Article
Additional Information: NIBR author: Cosulich, S institute: NIBR- address only contributor address: (Cumberbatch, Beran, Eckersley, Wang, Ellston, Dearden, Smith, Gray, Womack) AstraZeneca RandD, Oncology IMed, Mereside 33G83/197, Alderley Park, Macclesfield, Cheshire SK10 4TJ, United Kingdom (Blowers) Former AstraZeneca, Macclesfield, Cheshire, United Kingdom (Tang, Kim, Wistuba) Departments of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, United States (Behrens) Thoracic/Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, United States (Cosulich, Su, Fan) AstraZeneca, Asia and Emerging Markets IMed, Shanghai, China (Cosulich) Novartis Institutes for BioMedical Research, Basel, Switzerland (Kim) Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22648

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