Fibroblast Growth Factor Receptor 2-Her2 Transactivation: Role Of Fbroblasts In The Acquisition And Maintenance Of Anti-Her2 Target Therapies Resistance In Breast Cancer

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 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 DISCUSION We found that factors secreted by fibroblast can support cancer growth and progression by influencing and promoting the resistant phenotype. In our proposed model, HER2 positive BC cell lines resistant to Trastuzumab and Lapatinib have an active FGFR2 signalling pathway, able to maintain HER2 signalling by receptor transactivation. This bypasses HER2 inhibition and contributes to the maintenance of the cellular addiction to HER2 pathways even when the protein is being targeted, promoting cell proliferation and survival. Moreover, resistant cell lines secreted factors induced fibroblast activation and also modulated fibroblasts tumour promoting factors secretion pattern. As a result, after exposure to resistant cell lines secreted factors, fibroblasts become more efficient on promoting BC cell lines resistance. Similarly, the supernatant derived from fibroblasts isolated from HER2+ tumours was able to induce the activation of HER2 and FGFR2 pathways. The same effect was found in vivo, were co-injection with HER2+ tumour associated fibroblasts promoted tumour aggressiveness and resistance through HER2 and FGFR2 activation 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, Pedro Gascón, Pedro Gascón. Fibroblast growth factor receptor 2 - HER2 transactivation: Role of fbroblasts in the acquisition and maintenance of anti-Her2 target therapies resistance in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 752.