RET

  • Rearranged during transfection (RET)
  • Gene Location: chromosome 10 (10q11)

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

Etiology and Epidemiology

  • 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

When to Test:

  • Patients with gastric cancer should undergo testing for RET mutations and other relevant biomarkers at the time of diagnosis using next-generation sequencing (NGS) at the discretion of the physician.8

Available Testing Methods:

  • RET testing can be conducted using immunohistochemistry (IHC) or NGS. However, NGS is the preferred method, as IHC is less reliable for detecting RET alterations due to its low sensitivity and variable specificity.10,11

Guideline Recommendations for Testing:

  • Biomarker testing for gastric cancer should start with IHC and targeted PCR, followed by NGS testing. If tissue is limited or a biopsy isn't feasible, sequential single biomarker testing may deplete the sample. In these cases, comprehensive genomic profiling via a validated NGS assay is advised. Key biomarkers for interrogation include HER2 overexpression, PD-L1 expression, microsatellite instability, tumor mutational burden, NTRK fusion, RET fusion, and BRAF V600E mutation.9
Figure

RET Targeted Therapy

Approved Agents:

  • The only approved treatment for RET gene-fusion–positive gastric tumors is selpercatinib, approved in 2022.5,12-15
  • Selpercatinib has demonstrated antitumor activity against cells harboring constitutively active RET proteins from gene fusions and mutations.12,14
  • Selpercatinib is generally well tolerated with a permanent discontinuation rate of 8%.12,14

Selpercatinib12

  • FDA-Approved Indication:
    • Adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.
    • This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
  • Mechanism of Action:
    • Selpercatinib is a kinase inhibitor that inhibits wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3. Selpercatibib also inhibits FGFR 1, 2, and 3 at higher concentrations.
    • Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines.
    • In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T.
  • Drug Information:
  • Patient Resources:

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. Ferrara R, Auger N, Auclin E, et al. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol. 2018;13(1):27-45.
  11. Naidoo J, Drilon A. Molecular diagnostic testing in non-small cell lung cancer. Am J Hematol Oncol. 2014;10(4):4-11.
  12. RETEVMO (selpercatinib). Prescribing information. Eli Lilly and Company; 2022. Accessed May 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213246s008lbl.pdf
  13. 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
  14. 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
  15. 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