Targeting Specific P110α Isoform In ErbB2Overexpressing/PTEN-deficient Breast Cancer

Objectives Inactivation of the tumor suppressor PTEN was found in over40%HER2-positive breast cancers is relatived with poor clinical pronogsis. Reduced PTENactivity activates the downstream of PI3K/AKT signaling pathway. There are twoubiquitously expressed PI3K isforms p110α and p110β which are vital for PI3K/AKTsignaling pathway, while Most breast cancer cell lines are sensitive to inactivation of p110αand PTEN-deficient cancers is mediated by p110β. However, which isoform is essential forthis aggressive subtype of breast cancer,remains elusive. Detailed understanding of thegenetic abnormalities that drive this aggressive subset of breast cancer can lead todevelopment of highly specific inhibitors targeting key oncogenic pathways.Methods Effects of p110α or p110B ablation on mammary tumorigenesis in NIC-PTEN-/-mice was tested. Contribution of p110α and p110β inhibitors to the signaling Growth andSuivival of ErbB2Overexpression and PTEN Null Human Breast Cancer Cell Lines weretested in vitro and in vivo.Results PTEN Downregulation increases the tumor transformation induced by HER2overexpression in Vitro and in Vivo. p110α-deficiency rather than p110β-deficiency leadto decelerated tumor onset and lung metastesis in NIC-PTEN-/-genetic model. SignalingGrowth and Suivival of ErbB2Overexpression and PTEN Null Human Breast Cancer CellLines in vitro and in vivo in mediated by p110α rather than p110β inhibitor.Conclusions Our results provide specific targeting of PI3K isoform in HER2positive andPTEN-loss breast cancer, a particularly aggressive and currently incurable disease. Objectives Inactivation of the tumor suppressor PTEN was found in over40%HER2-positive breast cancers is relatived with poor clinical pronogsis. Reduced PTENactivity activates the downstream of PI3K/AKT signaling pathway which seems to be amajor determinant of Trastuzumab resistance in breast cancer. P110α isoform is essentialfor this aggressive subtype of breast cancer while if targeting P110a could rescue lapatinibresistance is unknown.Methods Dose-response curves were obtained by MTS ASSAY after72h exposure ofBT474and SKBR3cell lines to HER family targeting therapy-lapatinib with or withoutp110α inhibitors. we further confirmed this observation using two independent orthotopicxenograft models. HCC1569and BT474-sh-PTEN xenografts were treated with lapatinibor/and P110inhibitor.Results P110inhibitor restores lapatinib resistance in HER2overexpressing and PTENnull breast cancer cells by antagonizing the protective effect of PTEN deficiency onlapatinib’s antiproliferative effects. The sensitizing effect of A66was attributable to itsability to antagonizing the activation of PI3K/AKT and downstream signaling. Specificp110α inhibitor rescue PTEN loss-induced lapatinib resistance in vivo.Conclusions Our results provide evidence for combination therapy of targeting p110α andErbB2in ErbB2positive and PTEN-loss breast cancer, a particularly aggressive andcurrently incurable disease.