Abstract P6-11-17: Mutations in PIK3R1 activate multiple pathways in breast cancer

Abstract

Abstract It has been estimated that by the end of this year, 270,000 American women will be newly diagnosed with breast cancer, while 40,000 women that already have breast cancer will succumb to the disease. Considerable attention has been given to the PI3K signaling cascade following the discovery that PIK3CA is the most frequently mutated oncogene in breast cancer.However, few studies have explored the function of PIK3R1, which is the regulatory domain of the PI3K complex, despite being mutated in ~3% of all breast cancers. Several studies have demonstrated that expression of PIK3R1 is downregulated in human cancers. Decreased expression of the PIK3R1 protein leads to tumor formation, suggesting its role as a tumor suppressor gene and a potential prognostic marker in breast cancer. However, PIK3R1 is a gene with little pre-clinical evidence to recommend experimental therapies. Despite this lack of evidence, commercial services that perform molecular analyses of tumors suggest the use of an mTOR inhibitor for patients whose breast cancers carry mutant PIK3R1. In order to determine if mTOR inhibitors were indeed effective in mutant PIK3R1 tumors, we created and characterized a model for mutant PIK3R1 in the non-tumorigenic, human breast epithelial cell line, MCF-10A. Surprisingly, we observed that mTOR inhibitors were ineffective in these cells. However, in searching for other classes of small molecule inhibitors that were effective, we observed that mutations in PIK3R1 sensitized cells to MAPK inhibitors. Herein, we present the first evidence for the use of targeted therapies in breast cancers carrying mutant PIK3R1. We provide evidence against the use of mTOR inhibitors and provide a rationale for the use of MAPK inhibitors. Citation Format: Abukhdeir AM, Turturro SB, Najor MS, Brar SS, Cobleigh MA. Mutations in PIK3R1 activate multiple pathways in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-17.