Identification of a Subset of Human Non-Small Cell Lung Cancer Patients with High PI3K beta and Low PTEN Expression, More Prevalent in Squamous Cell Carcinoma

作者：Cumberbatch Marie^*; Tang Ximing; Beran Garry; Eckersley Sonia; Wang Xin; Ellston Rebecca P A; Dearden Simon; Cosulich Sabina; Smith Paul D; Behrens Carmen; Kim Edward S; Su Xinying; Fan Shuqiong; Gray Neil; Blowers David P; Wistuba Ignacio I; Womack Chris

来源：Clinical Cancer Research, 2014, 20(3): 595-603.

DOI：10.1158/1078-0432.CCR-13-1638

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 PI3K beta and its relation to PTEN in non-small cell lung cancer NSCLC remain unclear.
Experimental Design: Antibodies directed against PI3K beta 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 PI3K beta and PTEN were explored and colocalization of these markers in individual tumor cores were correlated.
Results: PI3K beta 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 PI3K beta 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 PI3K beta accompanied by a reduction/loss of PTEN, for whom selective PI3K beta inhibitors may be predicted to achieve greater clinical benefit.

• 出版日期2014-2-1