Herein, we show that a novel combination of HER2-targeted therapies, ganetespib and lapatinib, exhibits synergistic inhibition of HER signaling and the downstream PI3K/Akt and Ras/MEK/ERK pathways in both lapatinib-sensitive and resistant HER2 + breast cancer cells in vitro. Here, ERBB2 is linked to breast carcinoma.