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The RET gene

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The RET gene

What is RET?

The RET gene codes for a protein that plays an important role in cell growth, cell specialisation and nerve cell development in the body [1].

Why is it important?

The RET gene is altered in several types of salivary gland cancer [2, 3]. These changes often fuse one part of the RET gene with another gene, to create a new, faulty version of it [4]. This new fusion gene switches on signalling pathways which can drive cancer growth and reduce the effectiveness of cancer therapies [5, 6].

What is the evidence?

RET fusion genes such as CCDC6−RET, NCOA4−RET, ETV6-RET, TRIM27-RET, and TRIM33-RET have been found across multiple salivary gland cancer subtypes [2-4, 7].

Is RET a potential target for new treatments?

Since different RET fusions have been found across multiple salivary gland cancer subtypes, the RET protein is a strong candidate for targeted therapy [5].

In a small study, patients whose salivary gland cancer had the NCOA4-RET fusion showed a good response to a drug called cabozantinib. Cabozantinib is a drug that works on many targets, which means it may be more toxic and less effective than drugs that specifically target the RET protein [8].

A drug that specifically targets the RET protein called selpercatinib was tested on various cancer types in the Libretto trial, leading to its approval for cancers with RET alterations [9, 10]. This trial showed that patients responded well, and 2 of 4 patients with RET fusion salivary gland cancer saw a lasting response [10].

Useful resources

Read more about how to get your tumour profiled and add to a research biobank here:

References

  1. Zhao L, Wang N, Zhang D, Jia Y, Kong F. A comprehensive overview of the relationship between RET gene and tumor occurrence. Front Oncol. 2023; 13:1090757.
  2. Regua AT, Najjar M, Lo HW. RET signaling pathway and RET inhibitors in human cancer. Front Oncol. 2022; 12:932353.
  3. Skálová A, Vanecek T, Uro-Coste E, Bishop JA, Weinreb I, Thompson LDR, et al. Molecular Profiling of Salivary Gland Intraductal Carcinoma Revealed a Subset of Tumors Harboring NCOA4-RET and Novel TRIM27-RET Fusions: A Report of 17 cases. Am J Surg Pathol. 2018; 42(11):1445-55.
  4. Kutukova S, Imyanitov E, Beliak NP, Ivaskova JV, Razumova A. NTRK, ALK and RET rearrangements in salivary gland cancer. Journal of Clinical Oncology. 2021; 39(15_suppl):e18023-e.
  5. Sreenivasan S, Jiwani RA, White R, Bakalov V, Moll R, Liput J, et al. Advances in Targeted and Systemic Therapy for Salivary Gland Carcinomas: Current Options and Future Directions. Curr Oncol. 2025; 32(4).
  6. Clifton-Bligh RJ. Mechanisms of resistance to RET-directed therapies. Endocr Relat Cancer. 2025; 32(2).
  7. Weinreb I, Bishop JA, Chiosea SI, Seethala RR, Perez-Ordonez B, Zhang L, et al. Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland. Am J Surg Pathol. 2018; 42(4):442-52.
  8. van Boxtel W, Uijen MJM, Krens SD, Dijkema T, Willems SM, Jonker MA, et al. Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer. Eur J Cancer. 2022; 161:128-37.
  9. European Medicines Agency. selpercatinib. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/retsevmo#product-info (Accessed: 01/10/2025).
  10. Subbiah V, Wolf J, Konda B, Kang H, Spira A, Weiss J, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022; 23(10):1261-73.

Last Updated December 2025