RET rearrangements are actionable alterations in breast cancer

Bhavna Paratala ,Ellen Lee,Sonia Dolfi ,Siraj M Ali,Atul Kulkarni,Stephanie K Lin ,Kien Pham,Jon Chung ,Chen Liu,Jeffrey S Ross,Alexa B Schrock,Casey Williams ,Lorna Rodrı́guez-Rodrı́guez ,Brian Leyland‐Jones ,Shridar Ganesan,Frances Diclemente,Kirstin Williams,Whitney Petrosky,Ming Yao,Bahar Yilmazel,Kim M Hirshfield

doi:10.1038/s41467-018-07341-4

Bhavna Paratala , Ellen Lee + Show 19 more

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https://doi.org/10.1038/s41467-018-07341-4

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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.

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We report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer
The landscape of RET genomic alterations in 9693 breast cancer samples was assessed as part of hybrid capture-based next-generation sequencing of up to 405 cancer-related genes including select introns of up to 25 genes
RET alterations are reported from a large cohort of breast cancers that were genomically profiled as part of routine clinical care

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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. Multi-kinase inhibitors with activity against RET are FDA approved for thyroid cancers, and clinical trials are investigating their use in targeting RET fusions in lung and other solid cancers[5,6]

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