This forms an important part of the Pharmacological Audit Trail that  targeted drugs. 4.2. Selecting Patients Likely to Respond to PI3K Inhibitors As PI3K inhibitors A-769662 progress through the early clinical safety studies and into trials focusing on clinical efficacy, selection of the patient population most likely to benefit from treatment becomes an important consideration. A better understanding of drug sensitivity and resistance mechanisms is critical to the successful development and application of targeted cancer agents. A good example is the inherent resistance of tumours to anti EGFR antibody and small molecule therapies resulting from the presence of a KRAS mutation and the sensitivity of patients to the gefitinib and erlotinib EGFR inhibitors in non small cell lung cancer patients with activating EGFR mutations.
We have previously emphasised the importance AZD1480 of identifying predictive biomarkers to select patients that will be responsive or resistant to PI3K or PI3K/mTOR inhibitors. An overview and update is provided here. Boyd and colleagues have used reverse phase protein arrays, to profile the phosphorylation status of 100 proteins in a panel of 30 breast cancer cell lines. They found that sensitivity to the PI3K/mTOR inhibitor PI 103 was significantly correlated with elevated phosphorylation at key nodes in the PI3K/AKT/ mTOR pathway, including AKTTHR308, AKTSER473, PRASTHR246 and FKHRT24, suggesting that high levels of signalling through the pathway may be indicative of pathway addiction and be predictive of response to a targeted PI3K inhibitor.
A study by Dan and colleagues came to a similar conclusion in a screen of a panel of 39 cell lines, in which they observed that cancer cell lines with high AKTSER473 were more sensitive to a range of PI3K inhibitors from different chemotypes. However, there was no correlation observed between the level of AKT phosphorylation and PIK3CA mutation status. In a separate study, there was no correlation seen between extent of pathway inhibition and sensitivity to PI3K inhibitors such as PI 103 and GDC 0941. A number of studies with different PI3K inhibitors have demonstrated that tumours with activating PIK3CA mutations or loss of PTEN expression are responsive to PI3K inhibition in vitro and in vivo. Serra and colleagues demonstrated that NVPBEZ235 had activity in tumours with PI3K activating mutations.
Two studies with the early prototype non specific PI3K inhibitor LY294002 showed that cancer cell lines with PI3K mutations or, conversely, loss of PTEN expression showed increased sensitivity to PI3K inhibition. More recent studies with NVP BEZ235 or GDC 0941 have also shown that tumours with activating PIK3CA mutations exhibit increased sensitivity to PI3K inhibition. These observations would suggest that a patient group with activating PIK3CA mutations or loss of PTEN expression would be the most suitable for treatment with PI3K inhibitors. However, the predictive value is not completely clear as, within these studies, there are tumours without PIK3CA mutations or loss of PTEN expression that are also sensitive to PI3K inhibition.