Abstract B24: Targeting hyaluronan sensitizes breast cancer-associated fibroblasts to lapatinib and overcomes stromal resistance

Abstract

Abstract Tumors represent abnormal organs comprised not only of neoplastic cells, but also of normal cells and extracellular matrix (ECM). Therefore, clinical progression as well as response to therapies depends not only on properties of neoplastic cells, but also on the interactions between different types of cells within tumors. Cancer-associated fibroblasts (CAFs) are the major non-nenoplastic cell component of tumors and major the producers of ECM. Despite extensive research, mechanisms and consequences of interactions between breast carcinoma cells and CAFs remain insufficiently understood. Using organotypic 3d co-cultures between breast carcinoma cell lines representing different sub-types of the disease and CAFs, we interrogated changes in gene expression and metabolism that result from the interaction. We found that while contact with fibroblats induces robust changes in expression and metabolism, the majority of changes are subtype and cell line specific. Furthermore, we found that fibroblasts can provide a dramatic protection against dual EGFR/HER2 inhibitor lapatinib. Protective effect requires close contact between the two cell types in context of 3d culture, and is mediated by both reduced accumulation of the drug within carcinoma cells and elevated apoptotic threshold. Using synthetic lethality screens, we have identified several signaling pathways whose inhibition enhances cytotoxic effects of lapatinib. Interrogation of functional relevance of ECM has revealed that the stromal protection can be reversed by targeting hyaluronan, a major ECM component produced by fibroblasts. Rather than simply enhancing cytotoxic activity of lapatinib against carcinoma cells, hyaluronidase treatment sensitized CAFs to lapatinib, thereby removing the protective niche. Our studies shed light on molecular changes induced by the interaction with CAFs and offer novel approaches for overcoming microenvironmental protection by therapeutically targeting CAFs. Citation Format: Andriy Marusyk, Doris Tabassum, Jennifer Guerriero, Andrew Place, Andrii Rozhok, Antony Letai, Kornelia Polyak. Targeting hyaluronan sensitizes breast cancer-associated fibroblasts to lapatinib and overcomes stromal resistance. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B24.