loss of PTEN expression somewhat improved the development potential of BT474 cells when addressed at clinically relevant doses of lapatinib, which correlates with an increase in AKT activity.loss of PTEN expression also abrogated trastuzumab sensitivity. Critically, a second non-overlapping shRNA effective at inhibiting MAP kinase inhibitor PTEN expression, also conferred resistance to trastuzumab and lapatinib therefore fighting against an off target impact. An shRNA targeting GFP was employed as a negative control in most Eichhorn et al. Site 4 Cancer Res. Writer manuscript, available in PMC 2009 November 15. Trials. Interestingly, treatment with both trastuzumab and lapatinib conferred an advanced response to the growth potential of HER2 positive cells in comparison to either treatment alone, confirming the of others which have indicated that combining lapatinib with trastuzumab enhances their biological effect. But, while combination treatment with lapatinib and trastuzumab minimal cellular proliferation in PTEN knockdown cells, viable cells remained. To investigate the sensitivity of the PTEN knockdown cell lines to the different HER2 specific solutions we analysed the expansion potential Infectious causes of cancer of PTEN knockdown cells when handled with trastuzumab, lapatinib or both for 30 days. Treatment with HER2 led treatments totally inhibited the expansion potential of control cells. Nevertheless, the ablation of PTEN expression in cells reduced the growth inhibitory qualities of both trastuzumab and lapatinib. Collectively these data suggest that PTEN expression is needed for both lapatinib and trastuzumab sensitivity in cells. As has previously been reported lapatinib progress inhibition correlates with downregulation of HER2 dependent PI3K signalling. Thus, as a way to examine the results of lapatinib on PI3K signalling in cells which lack PTEN exercise, we treated BT474 cells or BT474 PTEN depleted cells with lapatinib. Indeed, similar heat shock protein inhibitor to trastuzumab, there was an important downregulation in phosphorylation in lapatinib treated control cells compared to untreated control cells. On the other hand downregulation of AKT phosphorylation was attenuated in lapatinib treated PTEN knockdown cells compared to lapatinib treated controls. However, unlike trastuzumab, no change was seen in MAPK phosphorylation upon treatment with lapatinib. In addition, treatment of cells with both trastuzumab and lapatinib resulted in an additive inhibitory influence on AKT action suggesting that trastuzumab and lapatinib may function through partially non-overlapping mechanisms to disrupt HER2 dependent PI3K signalling. The accepted dose in patients of lapatinib when found in combination with capecitabine is just a daily dose of 1250mg. This dosage in a minor plasma drug concentration of approximately 500 nM. Thus to test if PTEN reduction could overcome lapatinib sensitivity at clinically relevant concentrations we conducted a colony formation assay.