cabozantinib and Cell-Transformation--Neoplastic

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.

Topics: Anilides; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice; Mice, Nude; Mitogen-Activated Protein Kinases; NIH 3T3 Cells; Nuclear Receptor Coactivators; Oncogene Proteins, Fusion; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; ras Guanine Nucleotide Exchange Factors; Receptor, ErbB-2; Signal Transduction; Xenograft Model Antitumor Assays