our results are in line with recently reported findings utilising the anti HER2 monoclonal antibody trastuzumab. However it must be observed that while over-expression of wt PIK3CA decreased the effectiveness of trastuzumab in BT474 cells it was struggling to bypass the growth inhibitory properties of lapatinib, indicating that lapatinib Lonafarnib 193275-84-2 may work as one agent in individuals overexpressing wt PIK3CA. Lots of possibilities may explain the differing effect of PTEN loss and lapatinib resistance observed between our group and others, including the efficiency of PTEN knockdown in specific cell lines, the use of stably infected cell lines to determine the longterm effects of PTEN knockdown and lapatinib treatment, and that a 20 fold lower dose of lapatinib was found in the initial screen, reducing the chance of non specific effects. Be that as it might, a number of studies have revealed that PTEN reduction does not predict for lapatinib reaction in patients. Similar have been observed in trastuzumab resistance where no significant relationship has been observed in PTEN loss Lymphatic system and time to progression in trastuzumab treated patients. This data indicates that the larger cohort of patients might be needed in order to see differences in response in PTEN inferior tumours. One more reason could be the absence of a validated test to determine PTEN reduction in human tumours. It will be difficult to attempt to establish reliable medical correlations between PTEN reduction and reaction to lapatinib and other agents until a validated test becomes available. But, subsequent analysis incorporating PI3K status and equally PTEN status has plainly demonstrated the potential of PI3K process hyperactivation being a biomarker for trastuzumab efficacy. As a result, VX-661 it’ll be of critical importance to equally examine PI3K pathway hyperactivation as a predictor to lapatinib response. . Eichhorn et al. Site 8 Cancer Res. Author manuscript, obtainable in PMC 2009 November 15. Abnormal activation of the PI3K pathway is regular in breast cancer. Lack of function PTEN or PIK3CA strains have now been seen in about 250-based and 18% 40% of primary breast cancers, respectively. Bearing in mind the near mutual exclusivity between loss of function PTEN mutations and PI3K mutations, it’s maybe not surprising that deregulation of the PI3K pathway likely does occur in over 50% of breast cancers. Moreover, the presence of PI3K variations and a significant correlation between HER2 overexpression has been described. There are several potential implications of the observations. One inference is that PTEN position and the current presence of PI3K activating mutations ought to be taken into consideration in medical studies with anti HER2 agents simply because they can estimate for opposition. An additional consequence of our findings is the fact that hyperactivation of the PI3K pathway may be pharmacologically focused which could in turn result in reversal of lapatinib resistance.