Cancer-associated fibroblasts and response to anti-her2 monoclonal antibodies in breast cancer

Resumen

The development of anti-HER2 targeted therapies significantly changed the natural course of HER2-positive breast cancer. However, a proportion of patients will ultimately die on standard treatment with anti-HER2 therapies as a consequence of innate or acquired resistance mechanisms1. For this reason, understanding the molecular basis underlying anti-HER2 drug sensitivity and resistance is crucial to further advance towards it’s cure. In the last years, it has become evident that cancer-associated fibroblasts (CAFs; an abundant cell population within the tumour microenvironment (TME)), directly support tumorigenesis and promote therapy resistance2–5. Nonetheless, while much of CAF’s contributions have been documented in other type of solid tumours, their particular roles in HER2-positive breast cancer remains to be deeply understood. In this PhD work we have hypothesised that CAFs may play important roles on either innate or acquired resistance to anti-HER2 targeted agents. To approach this, we have performed pre-clinical studies, by assessing in vitro, in vivo as well as in patient’ samples the potential role of CAFs on such drug evasion. In this study we have showed that in HER2-positive breast cancer, CAFs promote drug evasion of HER2-positive breast cancer cells. Moreover, we have identified a potential stromal-driven mechanism by which CAFs would confer protective drug capacity to cancer cells. Bibliography: 1. Baselga, J. & Swain, S. M. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9, 463–475 (2009). 2. Fiori, M. E. et al. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol. Cancer 18, 70 (2019). 3. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–98 (2016). 4. Vaquero, J. et al. The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma. Clin. Cancer Res. 24, 4282–4296 (2018). 5. Brechbuhl, H. M. et al. Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen. Clin. Cancer Res. 23, 1710–1721 (2017).