Tumor Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation.

Purpose: Despite the therapeutic success of existing HER2 targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2 targeted therapies resistance. Experimental Design: We have used a platform of HER2 targeted therapies resistant cell lines and primary cultures of healthy and tumor associated fibroblast to identify new potential targets related to tumor escape from anti-HER2 therapies Results: We have shown that tumor associated fibroblasts (TAFs) promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5 that induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src leading to resistance to HER2 targeted therapies. In vivo, co-inoculating non-resistant cell lines with TAFs results in more aggressive and resistant tumors. Resistant cells activate fibroblasts and secrete FGFR ligands, creating a positive feedback loop that fuels resistance. FGFR2 inhibition not only inhibits HER2 activation, but also induces apoptosis in cells resistant to HER2-targeted therapies. In vivo, inhibitors of FGFR2 reverse resistance and re-sensitize resistant cells to HER2-targeted therapies. In HER2 patients9 samples, α-SMA, FGF5 and FGFR2 contribute to poor outcome and correlate with c-Src activation. Importantly, expression of FGF5 and phospho-HER2 correlated with a reduced pathologic complete response rate in patients with HER2 positive breast cancer treated with neoadjuvant trastuzumab which highlights the significant role of TAFs/FGF5 in HER2 breast cancer progression and resistance. Conclusions: We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2 targeted therapies resistance in breast cancer which can be reversed by FGFR inhibitors.