PIK3CA mutation and amplification in human lung cancer

Abstract

To explore the significance of phosphatidylinositol-3-kinase, catalytic, alpha (PIK3CA) in the carcinogenesis in human lung, mutations and copy number changes were investigated in 148 Japanese patients with primary cancer of the lung. For biological validation, the effects of exogenously expressed wild-type and mutated PIK3CA were studied in an immortalized human airway epithelial cell line. Mutations in PIK3CA were found in five (3.6%) of the 139 available patients, and copy number gains were found in 21 (18.3%) of 115 patients, respectively. Overall, mutations or copy number gains were detected in 24 of the 106 patients (22.6%) for whom results in both analyses were available. The prevalence of copy number gains was higher in men, smokers, and in patients with squamous cell carcinoma than in the opposite categories. The copy number changes showed a trend toward higher prevalence in the earlier stages (P = 0.038). Interestingly, the presence of mutations and of copy number alterations were mutually exclusive in the present patients, implying that both entail equivalent oncogenic potential. Over-expressed wild-type PIK3CA and its two common mutants, K545E and H1047R, significantly enhanced the anchorage-independent growth activity and migration activity of immortalized airway epithelium 16HBE14o-cells, but the effects of the K545E and H1047R mutants were more remarkable than those of the wild-type. The present demonstrates an important role of PIK3CA in human lung carcinogenesis.

Mutation and expression of multiple treatment response-related genes in a population with locally advanced non-small cell lung cancer

“…Mutations in PIK3CA were found in five (3.6%) of the 139 available patients. PIK3CA has two common mutants, K545E and H1047R (17). In our investigation, PIK3CA mutations were found in 3 patients (10%), including the PIK3CA codon 542, 545 and 1047 mutational sites, which was consistent with results reported by Okudela et al (17).…”

A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features

“…In contrast to the low frequency of mutations, PIK3CA copy number gains have been reported in 33.1% of squamous cell lung cancer and in 6.2% of lung adenocarcinomas (11). In vitro data indicates that PI3K signalling mediates bronchioalveolar stem cell expansion initiated by oncogenic K-RAS, whereas oncogenic PIK3CA mutations enhance the anchorage-independent growth and migration activity of immortalised respiratory epithelial cells (17). More importantly, the inhibition of PI3K/AKT/mTOR signalling through pharmacologic and genetic approaches induces the anti-proliferative effects on certain NSCLC cell lines, as well as in mouse models of lung cancer (12).…”

Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737

“…Although expression of Myc stimulates proliferation, it also provides a potent apoptotic stimulus (8). Perhaps as a result, SCLC is highly dependent on signaling from the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway, which is activated by growth factors, such as stem cell factor, insulin-like growth factor-I, or hepatocyte growth factor (9,10), or by genetic alterations in PTEN (11) or PIK3CA (12). Another prominent feature of SCLC is overexpression of antiapoptotic members of the Bcl-2 family (13), which regulate apoptosis mediated by the intrinsic or mitochondrial pathway (14).…”