Abstract P6-11-09: A preclinical study to demonstrate the utility of fulvestrant and MLN0128 combination against HR+ and HER2+ breast cancer

Abstract

Background: Up to 10% of total breast cancers are positive for both hormone receptor [HR: estrogen receptor (ER) and/or progesterone receptor (PR)] and HER2. These patients belong mainly to the luminal B subtype, which exhibits resistance to endocrine therapy. Currently, systemic treatment for HR+/HER2+ breast cancer patients involves a combination of chemotherapy and HER2-directed therapy. While these therapies improve outcomes, they are associated with pernicious side effects. Results and Discussion: As demonstrated by studies from a number of laboratories, in HR+/HER2+ cancer, ER is constitutively activated. In other words, the estrogen ligand is not needed for ER activation. The constitutively activated ER, through its non-genomic pathways, can stimulate both HER2 (a feed forward loop) and associated kinases. In patients with HR+/HER2+ tumors, genes in the PI3K and ER pathways have been altered. Activation of PI3K/Akt/mTOR by HER2 overexpression predicts tumor progression in breast cancer [Zhou et al., Clin Cancer Res. 10: 6779 (2004)]. Therefore, PI3k/AKT/mTOR is considered as an attractive therapeutic target for HR+/HER2+ breast cancer. Allosteric inhibitors of mTOR, such as RAD001 (Everlimus), only target mTORC1 but not mTORC2, relieving the negative feedback loop in this pathway, and leading to the activation of AKT. Our results suggest that to effectively treat HR+/HER2+ cancers, both mTORC1 and mTORC2 signaling must be suppressed. In these contexts; MLN0128 (i.e., INK128 or "MLN") is a new ATP-competitive inhibitor of mTOR. It targets both mTORC1 and mTORC2; and it does not interact with FKBP12 (an immunoregulatory protein). Consequently, MLN produces weaker immune-suppressing effects than everolimus. Results from our cell culture experiments reveal that MLN is twenty times more potent than everolimus against ER+/HER2+ cells. Furthermore, while MLN alone has been demonstrated to inhibit the proliferation of ER+/HER2+ cells, we have observed more benefits when it is used as part of a combination. Fulvestrant (ICI) by itself only suppresses the proliferation of ER+/HER2+ cells partially. However, when MLN and ICI are used together, our studies revealed a synergistic effect. In addition, HR+/HER2+ PDX models have been generated to identify novel molecular networks and to examine the in vivo action of new targeted therapies against HR+/HER2+ cancer. We not only have verified the synergistic effect of MLN and ICI combination in vivo, we also identified a set of important genes playing roles in the growth of HR+/HER2+ tumors through RNA-Seq analysis. Conclusion. Due to their synergistic and targeted action, this MLN and ICI combination could provide better clinical outcome and less side-effects to HR+/HER2+ breast cancer patients, compared to the currently available options in the clinics. Citation Format: Shang Victoria Wu, Hannah Lu, Masaya Kai, Noriko Kanaya, Thenhang Luu, Courtney Vito, Laura Kruper, Joanne Mortimer, Shiuan Chen. A preclinical study to demonstrate the utility of fulvestrant and MLN0128 combination against HR+ and HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-09.