An anti-EGFR antibody-drug conjugate overcomes resistance to HER2-targeted drugs

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved in 2013 to treat HER2+ breast cancer. Despite its efficacy in the clinic, some patients exhibit intrinsic or acquired resistance to such ADC. To characterize mechanisms of resistance to T-DM1, we isolated several HER2+ resistant clones derived from the HCC1954 HER2+ cell line. The isolated clones were different as per their transcriptomic profiles. However, all the T-DM1-resistant clones showed decreased HER2 levels. Yet, the clones were still oncogenically dependent on HER2, as indicated by knock down experiments. The decrease in HER2 expression caused acquired resistance to T-DM1 and to other anti-HER2 therapies. Antibody array analyses showed that the epidermal growth factor receptor (EGFR) was expressed in these T-DM1-resistant HCC1954 clones. Indeed, therapies targeting EGFR, particularly cetuximab-DM1, demonstrated a strong anti-proliferative action on cells with acquired resistance to T-DM1 and HER2 loss. The expression of EGFR in cells resistant to T-DM1 offers the possibility of using therapies directed to this receptor to combat resistance to anti-HER2 drugs and loss of HER2 overexpression.