RET

Rearranged during transfection (RET)

RET Biology

The RET gene was first discovered and characterized in 1985 on chromosome 10.1-5 RET encodes a transmembrane tyrosine kinase with multiple active extracellular sites including a cysteine-rich domain and cadherin-like domain 1 (CLD1), CLD2, CLD3, and CLD4.2-4 Under normal circumstances, RET protein is involved in the development of the kidneys and enteric nervous system as well as the homeostasis of neural, neuroendocrine, and hematopoietic cells.3-5

Four glial cell line–derived neurotrophic factor (GDNF) family ligands (GFL) are endogenous ligands for RET; these include GDNF, persephin, artemin, and neurturin.3-5 Rather than bind directly to RET proteins, GFLs first bind to GDNF family receptor-α (GFRα) coreceptors, and this complex mediates RET homodimerization.1,3-5 The activated complex autophosphorylates and activates signal transduction pathways MAPK, RAS, ERK, PI3K, AKT, phospholipase C-γ, and JAK-STAT.1-3,6

RET gene fusions are found most frequently in thyroid cancers and non–small cell lung cancer while the incidence in BTC is relatively low (1%-2%) among cancers overall and even lower among patients with BTC (< 1%).2,5-7

Oncogenic RET proteins are involved in tumor cell proliferation, invasion, differentiation, and migration, and oncogenesis occurs via 2 primary mechanisms.1,2,4,6,8 The first mechanism is via constitutive activation of kinase activity, and the second is chromosomal rearrangements that produce a chimeric protein fusion of the RET and dimerization domains.2,4

RET Testing

The National Comprehensive Cancer Network (NCCN) guidelines recommend testing for RET gene fusions for all patients with unresectable or metastatic gallbladder cancer, intrahepatic cholangiocarcinoma (CCA), and extrahepatic CCA.7 The preferred test is next-generation sequencing (NGS), because traditional testing methods have limited utility for detecting RET fusions.2,4,7,8

RET Targeted Therapy

Currently, the only FDA-approved treatment for adult patients with locally advanced or metastatic BTC tumors with a RET gene fusion is selpercatinib.1,7,9,10 Selpercatinib is a selective RET kinase inhibitor that inactivates wild-type RET and various mutated RET isoforms.9,10 Selpercatinib is well tolerated with a permanent discontinuation rate of 8% and a dose interruption rate of 64%.9

Pralsetinib is a selective RET tyrosine kinase inhibitor mentioned within NCCN guidelines for BTC but does not currently have approval for treating tumor-agnostic solid tumors including BTCs.7,11 Pralsetinib is recommended under certain circumstances as first-line or subsequent-line systemic therapy.7,11

Learn more about Selpercatinib >

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. doi:10.3389/fonc.2023.1090757
  2. Belli C, Penault-Llorca F, Ladanyi M, et al. ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol. 2021;32(3):337-350. doi:10.1016/j.annonc.2020.11.021
  3. Ibanez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5(2):a009134-a009134. doi:10.1101/cshperspect.a009134
  4. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: Lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-167. doi:10.1038/nrclinonc.2017.175
  5. Carlomagno F. Thyroid cancer: Role of RET and beyond. Eur Thyroid J. 2012;1(1):15-23. doi:10.1159/000336975
  6. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679
  7. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 1.2024. Accessed June 12, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  8. Shi M, Wang W, Zhang J, et al. Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing. Cancer Sci. 2022;113(1):308-318. doi:10.1111/cas.15181
  9. Retevmo. Prescribing information. Eli Lilly and Company; 2024. Accessed June 12, 2024. https://uspl.lilly.com/retevmo/retevmo.html#pi
  10. FDA D.I.S.C.O. Burst Edition: FDA approvals of Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive solid tumors, and Retevmo (selpercatinib) for adult patients with locally advanced or metastatic RET fusion-positive non-small cell lung cancer. FDA. November 7, 2022. Accessed April 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-retevmo-selpercatinib-adult-patients-locally-advanced-or
  11. Subbiah V, Hu MIN, Gainor JF, et al. Clinical activity of the RET inhibitor pralsetinib (BLU-667) in patients with RET fusion–positive solid tumors. J Clin Oncol. 2021;39(suppl 3):467. doi:10.1200/JCO.2021.39.3_suppl.467