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

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 PI3Kβ and its relation to PTEN in non–small cell lung cancer NSCLC remain unclear. Experimental Design 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.

Integration of genomic data analysis for demonstrating potential targets in the subgroup populations of squamous cell lung cancer patients

“…In summary, our analysis showed that a shorter smoking history and central localization of SCC tumors were related to a better survival outcome (Clus 1); while a long smoking history and peripheral distribution of tumors appeared to associate with a poor survival (Clus 2). Furthermore, our findings about the associations between survival outcomes and clinical factors in SCC patients are consistent with previous reports [24][25][26][27]. Moreover, statistical analysis on tobacco consuming history and initial age of diagnosis indicated that the old people with a long smoking history are more vulnerable.…”

“…These genes were also reported as genetic alterations in SCC in previous works [14,[24][25][26][27]. We then further analyzed the expression and methylation of those genes.…”

“…For example, PIK3CA is mutated and overexpressed in the group with poor survival. Other studies indicate mutant PIK3CA stimulates the AKT pathway and promotes cell growth in cancers [24][25][26]. Therefore, PIK3CA is a potent target for the treatment of SCC.…”

“…The candidate signatures were generated by looking for the most frequent genomic variables based on different top fusion notes. Then the final survival-specific signatures were uncovered by comparing with the known genetic alterations in SCC [24][25][26][27]. Based on the profiles of survival-specific signatures across the SCC patients, the novel survival subgroups of patients were unveiled, and the genomic feature analysis for individual subtype was performed to identify the promising targets for further diagnosis and treatment.…”

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

“…Interestingly, one of the more sensitive lines, MDA-MB-157, expressed mutant rac (16). Loss of PTEN expression is common across many tumor types, TNBC (9), prostate (10,11), head and neck (21), colorectal cancer (22,23), and squamous lung (24), suggesting that inhibitors of PI3Kb are relevant in many diseases. Gaining insight into why PTEN WT cells are sensitive will broaden the application of these differentiated PI3K inhibitors.…”