Abstract A182: PI3K inhibitors overcome resistance to HER2-targeted agents caused by PIK3CA mutations in HER2-amplified breast cancer cell lines

Abstract

Abstract Background: The mechanisms of resistance to HER2-targeted agents and the means to overcome them have not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells. We also tested potential usefulness of various inhibitors against molecules on PI3K signaling pathway. Materials and Methods: We examined the effects of CL-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab, humanized anti-HER2 monocloncal antibody, on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR). We also examined different PI3K pathway inhibitors that were PI3K inhibitor, m-TOR inhibitor, and PI3K/m-TOR dual inhibitor, on the same panel of cell lines. Results: Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 mg/ml trastuzumab: 58% versus 92%; p = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 M CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. All HER2-amplified cells showed detectable level of phosphorylated-Akt on serum-starved condition, while cell lines without PI3K pathway enhancement or HER2-amplification did not. Growth of all HER2-amplified cells was inhibited by PI3K pathway inhibitors regardless of PIK3CA genotype. PI3K/m-TOR dual inhibitor had much lower IC50 than the other PI3K pathway inhibitors, suggesting that complete blockade of phosphorylation of Akt and S6K may be required for maximal growth inhibition. Conclusions: PIK3CA mutations are associated with resistance to HER2-targeted agents. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy. PI3K inhibitors, especially PI3K/m-TOR dual inhibitor, are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A182.