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Ref Type | Journal Article | ||||||||||||
PMID | (30446652) | ||||||||||||
Authors | Paratala BS, Chung JH, Williams CB, Yilmazel B, Petrosky W, Williams K, Schrock AB, Gay LM, Lee E, Dolfi SC, Pham K, Lin S, Yao M, Kulkarni A, DiClemente F, Liu C, Rodriguez-Rodriguez L, Ganesan S, Ross JS, Ali SM, Leyland-Jones B, Hirshfield KM | ||||||||||||
Title | RET rearrangements are actionable alterations in breast cancer. | ||||||||||||
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Abstract Text | 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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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RET | C611R | missense | unknown | RET C611R lies within the extracellular domain of the Ret protein (UniProt.org). C611R has been identified in the scientific literature (PMID: 22747440, PMID: 30446652, PMID: 25163725), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2024). | |
RET | D925H | missense | unknown | RET D925H lies within the protein kinase domain of the Ret protein (UniProt.org). D925H has been identified in sequencing studies (PMID: 8825918, PMID: 30446652), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024). | |
RET | E232K | missense | unknown | RET E232K lies within the cadherin domain of the Ret protein (UniProt.org). E232K has been identified in sequencing studies (PMID: 30446652), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024). | |
RET | L633V | missense | unknown | RET L633V lies within the extracellular domain of the Ret protein (UniProt.org). L633V has been identified in the scientific literature (PMID: 30446652, PMID: 38378752), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024). | |
RET | S462L | missense | unknown | RET S462L lies within the extracellular domain of the Ret protein (UniProt.org). S462L has been identified in sequencing studies (PMID: 30446652), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024). | |
RET | V706M | missense | unknown | RET V706M lies within the cytoplasmic domain of the Ret protein (UniProt.org). V706M has been identified in sequencing studies (PMID: 27683183, PMID: 30446652, PMID: 34741450), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024). |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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RET over exp | Advanced Solid Tumor | predicted - sensitive | Cabozantinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Cometriq (Cabometyx, cabozantinib) treatment resulted in moderate tumor volume reduction in a cell line xenograft model of transformed cells overexpressing RET (PMID: 30446652). | 30446652 |