Abstract 648: Combined PI3K and MEK inhibition in patient-derived xenografts generated from recurrent triple negative breast cancer

Abstract

Abstract Both the PI3K and ERK pathways have become critical therapeutic targets due to their importance in breast cancer. Some triple negative breast cancers (TNBC) are sensitive to MEK inhibition due to the presence of RAS activation signatures. However, hyperactivation of PI3K signaling through PTEN loss impairs efficacy of MEK inhibitors in TNBC. On the other hand, it is likely that inhibition of PI3K in TNBC results in compensatory feedback activation of MEK, as previously observed in HER2 positive cell-line models. Therefore, combined inhibition of both PI3K and MEK would translate to optimal therapeutic efficacy in the clinic. We generated patient-derived xenografts (PDXs) of TNBC from patients with recurrent disease to assess the efficacy of this combined therapy in a model that more closely resembles the clinical scenario. Upon completion of informed patient consent, biopsies from patients with cutaneous, axillary or subclavicular metastases that had progressed from standard therapies were implanted in female nude mice. Five TBNC PDXs were expanded and confirmed to have equivalent pathological and morphological features as the original patient samples; they maintained similar ER, PR, HER2, PTEN and Ki67 status. Mutation status of PI3K, PTEN and RAS pathway were also evaluated. Additionally, the PTEN-loss transcriptional program and RAS-like transcriptional program were evaluated to further classify the tumors. PDXs were treated with a pan-class I PI3K inhibitor (NVP-BKM120) and a MEK inhibitor (AZD6244) as single agent or in combination. Preliminary tumor growth studies in a PDX that lacked PTEN expression demonstrated NVP-BKM120 sensitivity, but no response to AZD6244. The combination of NVP-BKM120 plus AZD6244 augmented the PI3K tumor inhibitory effect. Ongoing studies will more precisely delineate the relationship between pathway activation status and pharmacodynamic response to inhibitors targeting PI3K or MEK. These data highlight the great potential for evaluating new strategies in models that truly represent breast cancer of patients enrolling in clinical trials. In these studies we attained data from models that faithfully resemble the disease observed in the clinic supporting the advancement of clinical trials targeting both PI3K and Ras/Raf pathways in TNBC. Since these models strongly resemble the clinical disease, PDXs can also offer new opportunities to test experimental therapies that are normally hindered by the homogeneity and culture selection of standard cell-lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2011-648