Abstract 4761: Glial cell derived neurotrophic factor (GDNF)-RET signaling as a target in aromatase inhibitor resistant ER-positive breast cancers.

Abstract

Abstract The majority of breast cancers are estrogen receptor (ER)-positive and depend on estrogen for growth and survival. Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER-positive breast cancers. Despite providing substantial improvements in patient outcome, resistance to such therapy remains a major clinical challenge. We previously showed that GDNF-RET signaling plays an important role in ER-positive breast tumors and in the response to tamoxifen treatment. Resistance to this therapy is often associated with estrogen-independent activation of ER mediated by cell surface growth factor receptors, such as RET. Here, a multidisciplinary strategy was used to address the impact of GDNF-RET signaling in the response to AI treatment. First, using 2D and 3D in vitro approaches we show that GDNF-mediated RET signaling is enhanced in a model of AI resistance. Further, GDNF-RET signaling promotes the survival of AI-resistant cells and increases resistance in AI-sensitive cells, effects that are selectively reverted by a potent RET kinase inhibitor. Second, we generated a proliferation-independent GDNF-response gene set, identified from gene expression profiling in ER-positive breast cancer cells, and demonstrated this to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to AI treatment and development of resistance. Finally, the relevance of these findings was validated by demonstrating increased RET protein expression levels in an independent cohort of AI resistant patient samples. Together these preclinical and clinical models identify GDNF-RET signaling as a key determinant of response and resistance to AIs in ER-positive breast cancers. As a consequence, RET inhibition may be of use in the clinical setting either in combination with an AI to prevent and delay the onset of resistance, or to prolong the efficacy of the AI in the recurrent and/or metastatic setting. Citation Format: Andrea Morandi, Lesley-Ann Martin, Qiong Gao, Alan Mackay, David Robertson, Marketa Zvelebil, Mitch Dowsett, Ivan Plaza-Menacho, Clare M. Isacke. Glial cell derived neurotrophic factor (GDNF)-RET signaling as a target in aromatase inhibitor resistant ER-positive breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2013-4761