of p85 in adenocarcinoma compared to squamous cell carcinoma across all stages. High p85 expression was prognostic Alvocidib Flavopiridol of decreased survival on univariate analysis, but not on multivariate analysis, presumably due to the strong association with disease stage. Mutations or copy number gains of PIK3CA, the gene encoding p110a, have been described in lung cancer, and a limitation of our study is that the PIK3CA genetic status is unknown in the tumor specimens of our cohorts. However, the expression of p85 might be a more valuable indicator to study, as several studies have demonstrated that p110a that is expressed in excess of p85 is unstable and rapidly degraded when not bound to p85.
Immunohistochemical staining of tumor specimens for p110a is therefore likely going to underestimate the impact of p110a and changes in PIK3CA status. Furthermore, p85 has been proposed to Histamine Receptor have a regulatory function by associating with proteins other than p110 a such as IRS 1 and PTEN. Even tumor suppressor properties of p85 have been proposed based on observations in mice with a liver specific deletion of the PiK3r1 gene. We also cannot rule out the possibility that other isoforms of the catalytic subunit such as p110b, p110d and p110c might be involved in NSCLC as it has been described in other cancers. For instance, a recent study suggested a critical role for p110c in pancreatic cancer. Our findings are consistent with previous observations in a smaller cohort that included 73 cases of primary NSCLC which indicated that high p85 expression was associated with higher tumor grade and metastatic disease.
By using a quantitative method, we were able to confirm the correlation between high p85 expression and poor survival and higher stage in a large independent cohort of NSCLC patients. The association between high p85 expression and disease aggression demonstrated by our data and corroborated by results published by other investigators pointing to the role of PI3K in cancer, suggests that PI3K might be a valuable therapeutic target in NSCLC and warrants further investigation using novel and more effective PI3K inhibitors, such as those studied here. However, resistance to PI3K inhibition has been attributed to numerous mechanisms including negative feedback loops. One of the events downstream of PI3K activation is the activation of AKT through phosphorylation on Thr308 and Ser 473.
Increasing evidence has emerged that a rapamycin insensitive mTOR complex is the kinase responsible for AKT activation resulting from phosphorylation on Ser 473 which paradoxically allows mTOR to be both upstream and downstream of itself. It has been suggested that targeting the PI3K pathway at multiple sites might be required to interrupt feedback loops to achieve optimal outcomes. We were able to demonstrate synergistic effects by co targeting PI3K and mTOR in NSCLC cell lines using LY294002, a commercially available PI3K inhibitor, and NVP BKM12