Abstract A35: Proteomic and transcriptional profiling reveal differential responses to combined MEK and PI3K-mTOR network inhibition in basal-like and mesenchymal subtypes of triple negative breast cancer

摘要: Background: Activated MAPK and PI3K/AKT/mTOR pathway signaling are associated with poor prognosis in triple negative Breast cancer (TNBC). Therefore, suppression of both arms the MAPK/PI3K/AKT/mTOR network is a promising strategy for targeting TNBC. Here we explore anti-tumor effects combinations MEK inhibitor PI3K, AKT, or mTOR inhibitors focus on cell fate biomarker development two major subtypes TNBC, basal-like mesenchymal. Methods: Combinations PI3K inhibitor, AKT dual mTORC 1/2 rapalog were evaluated TNBC lines an orthotopically implanted patient-derived xenograft (PDX) model We utilized reverse-phase protein array (RPPA) quantitative real-time PCR to interrogate architecture transcriptional activity treated lines. Results: All synergistically suppress growth mesenchymal models. RPPA confirms that all common targets including pERK Th202/T204, pPRAS40 T246, pS6rp S235/236, p4E-BP1 S65 Notably, however, comparable repression produces distinct fates subtypes. Basal-like preferentially undergo delayed death surviving cells displaying profound arrest. In contrast, respond uniform quiescence exhibiting little no death. Transcriptional analysis corroborates these phenotypic demonstrating differential modulation genes regulating apoptosis proliferation versus Drug exhibit ‘reprogramming’ epithelial-mesenchymal status as evidenced by reduced gene expression inferring potential invasion metastasis. PDX paclitaxel resistant, early sustained tumor was achieved treating once daily GDC-0973, combination either GDC-0941, rapalog, Temsirolimus. Concurrent dosing this intense schedule some toxicity could likely be diminished dose modifications. Conclusions: These data highlight therapeutic combined inhibition chemo-resistant Importantly, they demonstrate innate differences response combinations, supporting concept molecular subtype will important predictor setting other targeted therapies. The GDC-0973 GDC-0941 performed particularly well taxane resistant deserves further evaluation clinical trials treatment Citation Format: Sarah J. Schweber, Alicia Rodriguez-Gabin, Jinghang Zhang, Valerie Calvert, Huiping Liu, Emanuel M. Petricoin, III, Eleni Andreopoulou, Susan Band Horwitz, Hayley McDaid. Proteomic profiling reveal responses PI3K-mTOR breast cancer. [abstract]. In: Proceedings AACR Special Conference: Targeting Network Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A35.