Abstract P5-08-02: New target in the resistant mechanism to trastuzumab

Abstract

Abstract Her2 positive (Her2+) breast cancer (BC) accounts for 18-20% of all breast cancer subtypes and is associated with high risk of death. Trastuzumab, the first Food and Drug Administration-approved targeted therapy for BC, represents a key milestone in the personalized treatment of Her2+ metastatic disease (Her2+ MBC). However, the median duration of response is less than a year, due to either primary or acquired resistance to the therapy. In addition, there is currently no conclusive biomarker for the response of patients to trastuzumab. Therefore, understanding the development of resistance to trastuzumab is of our interest. Recent studies have proposed various potential mechanisms leading to the resistance, including p27 rapid degradation. Previously, our study and other research demonstrated that Jab1 degrades p27 in breast cancer. These findings suggest that Jab1 over-expression contributes to trastuzumab resistance by facilitating p27 degradation. Jab1/CSN5 (c-Jun activation domain-binding protein 1) is over-expressed in 50% of primary and 90% of metastatic breast cancers, while its expression is low or absent in normal adult breast tissues. We previously identified that high expression of Jab1 is associated with shorter progression-free survival in breast cancer patients. In this study, our preliminary data showed that the knockdown of Jab1 sensitizes the breast cancer cells to trastuzumab treatment in a dose-dependent manner. Mechanistically, we found that Jab1 over-expression is significantly correlated with the activation of Akt pathway in Her2+ breast cancer cells and xenograft model. Interestingly, activated Akt, due to PTEN loss or PI3K activating mutation has been widely implicated in the potential mechanism to trastuzumab resistance. Therefore, our results suggest that targeting Jab1 overcomes the resistance to trastuzumab via interfering with PI3K/Akt pathway. In general, our study identifies Jab1 as a novel contributor to trastuzumab resistance and elucidates its potential mechanisms of actions. The successful completion of the study can potentially be translated to the clinic for the benefit of patients refractory to the therapy. Also our study suggests Jab1 expression level can be used as a predictive marker for trastuzumab treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-02.