RET rearrangements are actionable alterations in breast cancer

• Published in: Nature communications 2018-11, Vol.9 (1), p.4821-13, Article 4821
• Main Authors: Paratala, Bhavna S., Chung, Jon H., Williams, Casey B., Yilmazel, Bahar, Petrosky, Whitney, Williams, Kirstin, Schrock, Alexa B., Gay, Laurie M., Lee, Ellen, Dolfi, Sonia C., Pham, Kien, Lin, Stephanie, Yao, Ming, Kulkarni, Atul, DiClemente, Frances, Liu, Chen, Rodriguez-Rodriguez, Lorna, Ganesan, Shridar, Ross, Jeffrey S., Ali, Siraj M., Leyland-Jones, Brian, Hirshfield, Kim M.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/51; 13/56; 13/95; 38/22; 38/90; 42/109; 42/44; 45; 45/23; 45/70; 45/71; 45/77; 45/88; 45/91; 631/67/1059; 631/67/1347; 631/67/1857; 631/67/69; 631/67/70; 64/60; 82/29; 96/63; Amplification; Anilides - pharmacology; Animals; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; ErbB-2 protein; Female; Gene Expression Regulation, Neoplastic; Genetic transformation; Humanities and Social Sciences; Humans; Lungs; MAP kinase; MCF-7 Cells; Metastases; Mice; Mice, Nude; Missense mutation; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; Mutation; NIH 3T3 Cells; Nuclear Receptor Coactivators - genetics; Nuclear Receptor Coactivators - metabolism; Oncogene Proteins, Fusion - antagonists & inhibitors; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Piperidines - pharmacology; Proto-Oncogene Proteins c-ret - antagonists & inhibitors; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; Pyridines - pharmacology; Quinazolines - pharmacology; ras Guanine Nucleotide Exchange Factors - genetics; ras Guanine Nucleotide Exchange Factors - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Ret protein; Science; Science (multidisciplinary); Signal Transduction; Therapeutic applications; Thyroid; Tyrosine kinase inhibitors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07341-4

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. Fusions of the gene RET have been described in thyroid and lung cancers. Here, the AUs identify RET gene alterations, including known fusions, novel fusions, and rearrangements in breast cancer (BC) that are involved in the tumorigenic process and show the benefit of RET therapy in a recurrent BC patient carrying the NCOA4-RET fusion.