ONCOGENIC PROPERTIES AND TARGETING OF NTRK1 IN BREAST CANCER

Abstract

Triple negative breast cancers (TNBC) comprise a highly aggressive cancer subtype with high mortality rates, high frequency of metastatic disease and a lack of targeted therapies. A fraction of these cancers also demonstrate amplification of the NTRK1 gene. The protein product of the NTRK1 gene, TrkA, is a receptor tyrosine kinase (RTK) that recognizes neuronal growth factor (NGF) leading to downstream signaling through MAPK and other pathways that promote survival and proliferation. Pan-Trk inhibitors have been developed against rare cancers with NTRK translocations that result in constitutive Trk kinase activity. Expansion of these inhibitors’ application to amplifications, particularly in TNBC, offers the potential for targeted therapies. Here, we engineered non-tumorigenic immortalized human mammary epithelial cell lines and human breast cancer cell lines to overexpress TrkA. Overexpressing clones demonstrated cancerous and pro-metastatic phenotypes, which were reversed upon exposure to the Trk inhibitor larotrectinib. In vitro, the MCF10A and hTERT-IMEC engineered cell lines showed growth factor independence, increased downstream proliferative and pro-survival signaling, alterations in three-dimensional culture, and migratory phenotypes in increased wound healing and microchannel migration. In vivo, TrkA-overexpressing MCF7 cells showed increased tumor growth and acquired the capacity to establish disseminated disease. Our results demonstrate the potential clinical utility of larotrectinib for targeting NTRK1 amplified breast cancers and inhibiting metastasis.