TRAIL receptor activation overcomes resistance to trastuzumab in HER2 positive breast cancer cells

During the last few years and thanks to the development of new targeted therapies, the prognosis of patients diagnosed with breast cancer overexpressing HER2 has clearly improved. Nonetheless, it is frequent to find patients in which after a time of response to these therapies, tumors progress due to the development of resistances. Identifying the mechanisms leading to those resistances as well as new therapeutic strategies in that context represents nowadays an important challenge in the oncology clinic. With this purpose a new model of in vitro resistance to trastuzumab was generated in the laboratory based on the continuous culture with this drug. The prototypical BT474 HER2+ breast cancer cell line was plated at low density and grown in the presence of 50 nM trastuzumab (7.5 mg/ml) for 6 months. Trastuzumab-resistant cells were pooled, generating a cell population that was named BT-RH (for “Resistant to Herceptin™”). BT-RH cells were maintained in the presence (BT-RH+) or absence (BT-RH-) for an additional 6 months period. BT-RH- cells grew similarly in the presence or absence of trastuzumab. The acquired resistance obtained in BT-RH- cells was stable and quantitatively analogous to the resistance of BT-RH+ cells.