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