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Significance Factors stemming from the tumor microenvironment can modulate drug resistance. Therefore, rational approaches to design efficacious targeted therapies are needed. Here, we show that fibroblasts reduce lapatinib sensitivity in a subset of HER2+ breast cancer cells via paracrine signaling that can be reversed by targeting downstream survival programs such as MTOR and antiapoptotic proteins (BCL-XL and MCL-1). Our finding that fibroblasts derived from either primary tumor or metastatic sites limit lapatinib response has important implications for developing treatment strategies that can restore sensitivity in multiple drug-resistant microenvironments. Due to the diversity of microenvironmental factors between these sites, targeting downstream survival programs instead of individual factors released by fibroblasts represents a promising strategy to combat microenvironment complexity.

Fibroblast–tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways