RET

Rearranged during transfection (RET)

RET Biology

The rearranged during transfection (RET) gene is a DNA sequence localized to chromosome 10.1-5 It encodes a glycoprotein membrane receptor with tyrosine kinase activity with 4 cadherin-like domains (CLDs) and a cysteine-rich domain in the extracellular region.1,4 CLDs are involved in calcium-mediated cellular adhesions.4 The RET kinase is critical for developing the enteric nervous system during embryogenesis, including thyroid C cells, enteric ganglia, peripheral nervous system (PNS) ganglia, fetal kidney cells, and testes germ cells.2-4

The endogenous ligand for RET protein is glial cell line-derived neurotrophic factor (GDNF), a growth factor-like protein; persephin, neurturin, and artemin.2,4,5 These ligands do not agonize RET directly but instead attach to a co-receptor GDNF family receptor-α (GDNFα) protein.2,4 After activation, RET homodimerizes, which leads to autophosphorylation of tyrosine residues and activation of multiple signal pathways, including PI3K, MAPK, phospholipase C-γ, JAK-STAT, and PKA.1-4,6

RET fusions and rearrangements are present in 0%-2% of solid tumors and are found most commonly in cases of medullary thyroid cancer (>80%) due to their crucial role in the formation of thyroid C cells.1,2,6 The occurrence of RET fusions in gastric cancer is even more rare and is <1% of cases.7

The most common RET breakpoints occur in intron 11, followed by introns 10 and 7.3,8 Oncogenesis can occur via several mechanisms, including the alteration of transcriptional control or via fusion partners that dimerize RET proteins independently of endogenous ligands, which leads to constitutive expression.1-3

RET Testing

The National Comprehensive Cancer Network guidelines recommend next-generation sequencing (NGS) to detect RET gene fusions and other genetic markers.8,9 Traditional biomarker testing methods should be utilized first for more common biomarkers in gastric cancer, but they have somewhat limited utility for detecting RET variants.7-9 NGS testing for circulating tumor DNA is also viable.7

RET Targeted Therapy

The only approved treatment for RET gene-fusion–positive gastric tumors is selpercatinib, approved in 2022.5,10-13 Selpercatinib is a kinase inhibitor that attaches to wild-type RET, mutated RET isoforms, VEGFR1, and VEGFR2.10 Selpercatinib has demonstrated antitumor activity against cells harboring constitutively active RET proteins from gene fusions and mutations.10,12 Selpercatinib is generally well tolerated with a permanent discontinuation rate of 8%.10,12

Learn more about Selpercatinib >

References

  1. 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
  2. Carlomagno F. Thyroid cancer: role of RET and beyond. Eur Thyroid J. 2012;1(1):15-23. doi:10.1159/000336975
  3. 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
  4. 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
  5. 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
  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. Skórzewska M, Gęca K, Polkowski WP. A clinical viewpoint on the use of targeted therapy in advanced gastric cancer. Cancers. 2023;15(22):5490. doi:10.3390/cancers15225490
  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. National Comprehensive Cancer Network. NCCN guidelines version 1.2024: gastric cancer. May 29, 2024. Accessed May 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
  10. RETEVMO (selpercatinib). Prescribing information. Eli Lilly and Company; 2022. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213246s008lbl.pdf
  11. 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. Updated 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
  12. Subbiah V, Wolf J, Konda B, 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):1261-1273. doi:10.1016/S1470-2045(22)00541-1
  13. Li JJ, Rogers JE, Yamashita K, Waters RE, Blum Murphy M, Ajani JA. Therapeutic advances in the treatment of gastroesophageal cancers. Biomolecules. 2023;13(5):796. doi:10.3390/biom13050796