In vitro and in vivo scientific studies have demonstrated that lapatinib can proficiently inhibit the growth of trastuzumab-resistant breast cancer cell lines and tumor xenografts that express p95 ErbB2,presumably due to the fact lapatinib targets the intracellular tyrosine kinase part of ErbB2.Trastuzumab resistance might possibly also be mediated in some ErbB2t breast tumors by a rise in PI3K/Akt signaling related to either the loss or inactivation of PTEN expression or PI3KCA mutation.Presence of PTEN is related to tumor suppressor MEK Inhibitor selleck chemicals action.Loss of PTEN appears to counteract the anti-tumor effects of trastuzumab by marketing PI3K/Akt activation,which,in turn,stimulates tumor cell growth.In vitro research in PTEN-deficient ErbB2t breast tumor cell lines showed that tumor cells remained responsive to lapatinib and that lapatinib sensitivity appeared to become PTEN-independent.Transfection of ErbB2-overexpressing cell lines with mutant PI3KCA or wild-type PI3KCA resulted in trastuzumab resistance,suggesting that activation in the PI3K signaling pathway by PI3KCA mutation appeared to mediate resistance.Further,oncogenic mutations of PI3KCA,recognized in a number of numerous ErbB2t human breast cancer cell lines,are linked to trastuzumab resistance in vitro.
Contrary to earlier preclinical findings that showed that lapatinib sensitivity was PTEN-independent,a current in vitro study has proven that HA-1077 hyperactivation in the PI3K pathway by either loss-of-function mutations in PTEN or PI3KCA mutation may possibly also confer resistance to lapatinib in breast cancer cell lines.A further current in vitro research found that isolated clones of ErbB2t breast cancer cell lines with acquired resistance to lapatinib were also cross-resistant to trastuzumab and exhibited enhanced expression of AXL,a receptor tyrosine kinase.This choosing suggests that upregulation of AXL may be a novel mechanism concerned during the advancement of lapatinib and trastuzumab resistance.Additional preclinical research are essential to determine the function of PI3K activation and AXL upregulation in modulating lapatinib and trastuzumab resistance.Lapatinib has however for being investigated in other molecular mechanisms of trastuzumab resistance,for instance MUC4-mediated resistance.Preclinical scientific studies have proven the overexpression within the membrane-bound mucin glycoprotein,MUC4,in the trastuzumab-resistant human cell line,interferes with the binding of trastuzumab to ErbB2.Tumors that overexpress MUC4 may possibly possibly encourage tumorigenesis by activating ErbB2,suppressing apoptosis and inhibiting immune recognition of tumor cells.Collectively,the outcomes from these and other preclinical research provided a powerful scientific rationale for the carry out of clinical scientific studies with lapatinib in patients with trastuzumab-resistant ErbB2t breast cancer.