Abstract B69: Acquisition and maintenance of anti-Her2 target therapies resistance in breast cancer: Role of fibrobroblasts

Abstract

Abstract Introduction: Mechanisms underlying tumor progression after chemotherapy are not well understood. Therapeutic treatments can favor the clonal selection of cells with unique properties and different fitness for a given microenvironment. Indeed, tumor cells can induce changes in the structure and composition of the microenvironment to support their growth and spread. Our aim is to study if clonal selection induced by target therapies like Trastuzumab and Lapatinib favors the outgrowth of cells with different microenvironmental crosstalk capability, and in particular the role of fibroblast in the selection of these particular clones. Materials and Methods: In order to investigate if clonal selection induced by target therapies like Trastuzumab and Lapatinib favors the outgrowth of cells with different capability of microenvironmental crosstalk, we developed different cell lines resistant to these drugs from the parental SKBR3, BT474 and MDA-MB-453 Her2+ cells lines. We determined their molecular profile and investigated the changes in the expression of selected genes codifying soluble factors known to induce stromal changes, like chemokines, cytokines, matrix remodeling-related enzymes, angiogenic and neurogenic factors. To study the role of fibroblast in the selection of the resistant clones, and the crosstalk between these two populations, we developed fibroblast immortalized lines derived from breast cancer tumors and normal breast tissue, and study the effect of the fibroblasts in resistant induction, as well as the effect of resistant clones in the fibroblast activation. Results and Discussion: We observed that the major changes in the genes investigated were obtained in the Lapatinib resistant cell lines, suggesting that the acquisition of Lapatinib resistance can provide the tumor with a higher capability of stromal interaction. In vivo, the resistant cell lines showed an invasive growth pattern and higher angiogenesis compared to the parental cell lines. We observed a different pattern of fibroblast distribution in the tumors derived from the resistant cell lines, which display a more infiltrative distribution. The resistant tumors were also more fibroblast-enriched suggesting a higher microenvironment crosstalk capacity. In vitro, we found that the supernatant of breast cancer associated fibroblast was able to induce an increase in the resistant phenotype of parental lines, and that the resistant cell lines were able to induce a slightly activation of fibroblasts. Conclusion: These results highlight the importance of microenvironment in supporting tumor progression after chemotherapy. Citation Format: Patricia Fernandez-Nogueira, Mario Mancino, Gemma Fuster, Estel Enreig, Elisabeth Ametller, Paloma Bragado, Vanessa Almendro, Pere Gascon. Acquisition and maintenance of anti-Her2 target therapies resistance in breast cancer: Role of fibrobroblasts. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B69.