Activation of the unfolded protein response bypasses trastuzumab-mediated inhibition of the PI-3K pathway

HER2-positive breast cancer initially responds to trastuzumab treatment, but over time, resistance develops and rapid cancer progression occurs, for which various explanations have been proposed. Here we tested the hypothesis that induction of the unfolded protein response (UPR) could override HER2 inhibition by trastuzumab, leading to the re-activation of growth signaling and the activation of the downstream target Lipocalin 2 (LCN2). Trastuzumab significantly inhibited the basal expression of LCN2 in HER2 + SKBr3 human breast cancer cells. The induction of the UPR completely abrogated trastuzumab-mediated LCN2 downregulation, and, in fact caused an increase in transcription and secretion of LCN2 over baseline. Reduction of the UPR using 4-phenyl butyric acid (PBA) a chemical chaperone that ameliorates ER stress, restored trastuzumab-mediated inhibition. Inhibition of the PI3K/AKT signaling pathway in trastuzumab-treated/UPR-induced SKBr3 cells partially reduced the upregulation of LCN2. These results suggest that the UPR is a possible way to override the effect of trastuzumab in HER2+ cancer cells.

► The current standard of care of HER2+ breast cancers is trastuzumab.
► Resistance to trastuzumab is hallmarked by activation of PI3K/AKT signaling.
► The ER stress responses overrides trastuzumab inhibition of PI3K/AKT signaling.
► LCN2 is a putative downstream effector of tumor progression regulated by NF-κB and PI3K/AKT.