LAUSR

Significance Breast cancers that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ breast cancer have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have found that inhibition of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, sensitizes HER2+ breast cancers to HER2-targeting drugs, overcoming and preventing drug resistance, both in vitro and in vivo. These results suggest that combining HER2 and CDK8/19-targeting drugs could greatly improve the treatment outcome in metastatic HER2+ breast cancer.