Abstract IA04: Stroma-driven resistance to PI3K/mTOR inhibition

Abstract

Abstract PI3/mTOR pathway, a major regulator of cellular growth and metabolism, is mutated in ~70% of breast cancers and conveys resistance towards estrogen receptor- and HER2-targeted therapies. Unfortunately, targeting the PI3K pathway in the clinic has been hampered by emergence of drug resistance, often through rewiring of their signaling pathways rather than through mutations, a phenomenon called adaptive resistance that is often observed with targeted therapies. Our previous data have shown that adaptive resistance requires input from the tumor microenvironment. Cancer cells require the presence of extracellular matrix proteins to elicit drug resistance; without matrix contact the tumor cells died. Our data also show that fibroblasts secrete matrix proteins that increase cellular survival of epithelial cells under starvation and PI3K and mTOR inhibition. To investigate the identity and role of the secreted proteins that drive resistance, we performed mass-spectrometry and cytokine analysis of fibroblast secretomes treated with PI3K inhibitors. These data have identified several candidate proteins as potential drivers of stroma-mediated drug resistance, and we will discuss how targeting these proteins can increase the efficacy of PI3K- and mTOR-targeted therapies. Citation Format: Taru Muranen. Stroma-driven resistance to PI3K/mTOR inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA04.