The
insulin-like growth factor (
IGF) 1 receptor (IGF1R) is an important therapeutic target under study in many
cancers. Here, we describe a
breast cancer model based on expression of the ETV6-NTRK3 (EN) chimeric
tyrosine kinase that suggests novel therapeutic applications of IGF1R inhibitors in secretory breast
cancers. Originally discovered in congenital
fibrosarcomas with t(12;15) translocations, EN was identified subsequently in
secretory breast carcinoma (SBC) which represent a variant of invasive
ductal carcinoma. Because fibroblast transformation by EN requires the IGF1R axis, we hypothesized a similar dependency may exist in mammary cells and, if so, that IGF1R inhibitors might be useful to block EN-driven breast
oncogenesis. In this study, we analyzed EN expressing murine and human mammary epithelial cell lines for transformation properties. Various IGF1R signaling inhibitors, including the dual specificity IGF1R/
insulin receptor (INSR) inhibitor
BMS-536924, were then tested for effects on three-dimensional
Matrigel cell growth, migration, and
tumor formation. We found that EN expression increased acinar size and
luminal filling in
Matrigel cultures and promoted orthotopic
tumor growth in mice.
Tumors were well differentiated and nonmetastatic, similar to human SBC. The known EN effector pathway, PI3K-Akt, was activated in an IGF1- or
insulin-dependent manner.
BMS-536924 blocked EN transformation in vitro, whereas
BMS-754807, another IGIFR/INSR
kinase inhibitor currently in clinical trials, significantly reduced
tumor growth in vivo. Importantly, EN model systems mimic the clinical phenotype observed in human SBC. Moreover, EN has a strict requirement for IGF1R or INSR in breast cell transformation. Thus, our findings strongly encourage the evaluation of IGF1R/INSR inhibitors to treat EN-driven breast
cancers.