RET

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

RET Biology

  • The rearranged during transfection (RET) protein is a tyrosine kinase involved in multiple cellular processes, including proliferation, differentiation, survival, motility, and migration.1-4
  • There are 4 known endogenous ligands, including glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin.1,3,5
  • Ligands bind to glycosylphosphatidylinositol-anchored co-receptor molecules, called GFRα, and the co-receptor complex presents to RET, inducing homodimerization.2-5
  • Homodimerized RET causes autophosphorylation, which activates signal transduction pathways RAS-MAPK, JAK-STAT, PKC, PI3K-AKT, PLCγ, and PKC.1-6
  • The RET gene is located on chromosome 10 and encodes a transmembrane tyrosine kinase and proto-oncogene.1-4
  • RET contains intracellular, transmembrane, and extracellular domains.2,4,5
  • The extracellular region contains cysteine-rich domains and cadherin-like domains (involved in dimerization and are, thus, mutation targets.4

Etiology and Epidemiology

  • Hepatocellular carcinoma (HCC) patients with RET gene fusion have a poorer duration of response and overall survival compared to wild-type tumors.7
  • RET rearrangement likely occurs because of broken repair mechanisms after DNA double-strand breaks, which can occur via cell-extrinsic or cell-intrinsic factors.4
  • Breakpoints occur more frequently at intron 11, but some involve introns 7 and 10.4
  • In some cases, the partner fusion gene is constitutively expressed, so RET tyrosine kinase activity is increased.2-4
  • In other cases, the fusion contains a dimerization domain that activates RET in a ligand-independent manner.2-4
  • RET alterations are rare in hepatocellular carcinoma (HCC), with an occurrence rate of less than 0.1%.8

RET Testing

Available Testing Methods:

  • RNA-sequencing next-generation sequencing (NGS) has high sensitivity and specificity and can detect RET expression, while other testing modalities currently have limited utility.2,4
  • In cases where NGS is unavailable, the European Society for Medical Oncology (ESMO) recommends fluorescence in situ hybridization or reverse transcription polymerase chain reaction (RT-PCR).2

Guideline Recommendations for Testing:

  • National Comprehensive Cancer Network guidelines currently have no established indication for molecular profiling in HCC, but it may be warranted in some instances with unusual or atypical presentation.9

RET-Targeted Therapy

Approved Agents:

  • Selpercatinib is FDA-approved for the treatment of patients with locally advanced or metastatic HCC solid tumors with a RET gene fusion who have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.10,11
  • Selpercatinib is approved under accelerated approval based on the results of the phase I/II study LIBRETTO-001 (NCT03157128).10-12 Among 41 patients with advanced solid tumors, the overall response rate was 44% with a median duration of response of 24.5 months, and 67% of patients had a response at 6 months or longer.10-12 Selpercatinib was well tolerated, with only 8% of patients discontinuing permanently due to an adverse reaction.10-12

Mechanism of Action:

  • Selpercatinib is a selective tyrosine kinase inhibitor that inactivates wild-type RET, RET isoforms, VEGFR1, VEGFR2, and FGFR1-3.10

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. Carlomagno F. Thyroid cancer: role of RET and beyond. Eur Thyroid J. 2012;1(1):15-23. doi:10.1159/000336975
  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. Hua S. Physiological and pharmaceutical considerations for rectal drug formulations. Front Pharmacol. 2019;10:1196. doi:10.3389/fphar.2019.01196
  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. Ye S, Zhao XY, Hu XG, et al. TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in hepatocellular carcinoma. Oncol Rep. 2017;37(4):2215-2226. doi:10.3892/or.2017.5494
  8. Shi M, Wang W, Zhang J, Li B, Lv D, Wang D, Wang S, Cheng D, Ma T. 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: hepatocellular carcinoma. https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf
  10. RETEVMO (selpercatinib). Prescribing information. Eli Lilly and Company; 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213246s008lbl.pdf
  11. 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
  12. 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