RET

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

RET Biology

  • The RET gene is a novel target for pancreatic solid tumors.1,2
  • RET is involved in developing the kidney and the nervous systems; it plays a vital role in cell development, proliferation, migration, and differentiation.3-5
  • RET is located on chromosome 10, measures 60 kb, and contains 21 exons.3,6,7
  • Under normal cellular conditions, the RET protein binds endogenous ligands that cause homodimerization, autophosphorylation, and activation of multiple signal transduction pathways, including JAK-STAT, PKA, MAPK, PI3K, PLCγ, and PKC.3,4,6,7
  • Unlike many other receptor tyrosine kinases, RET does not bind directly to its ligands but to a ligand–coreceptor complex.4,5,7 Glial-line derived neurotrophic factor (GDNF), neurturin, persephin, and artemin are endogenous ligands that bind to GDNF family receptor-α (GFRα) coreceptors.3,4,7
  • RET encodes a transmembrane tyrosine kinase with 3 domains: the intracellular, transmembrane, and extracellular domains.3-7
  • Of interest to clinicians is the extracellular domain; this area contains a cysteine-rich domain and cadherin-like domains 1-4 (CDL1-4), which are mutation hotspots for the proto-oncogene.4,5,7

Etiology and Epidemiology

  • RET fusions cause oncogenesis in 1 of 2 primary ways: chimeric fusion with increased transcriptional control or upstream fusion of a homodimerization domain that results in ligand-independent autophosphorylation.5-7
  • RET fusions are uncommon in pancreatic cancer—they present in approximately 0.6% of tumor lines.8,9
  • Pancreatic ductal adenocarcinoma (PDAC) cell lines with RET isoforms display increased tumor aggressiveness secondary to perineural invasion.10
  • High RET expression is also associated with better overall survival in PDAC but increased tumor aggression and poorer prognosis.

RET Testing

When to Test:

  • Testing is recommended for patients with locally advanced or metastatic pancreatic cancer who are candidates for anticancer therapy.11

Available Testing Methods:

  • Testing is typically performed via next generation sequencing (NGS), with RNA-based NGS being the preferred method due to improved detection of gene fusions.11

Guidelines Recommendations for Testing:

  • The National Comprehensive Cancer Network guidelines do not make specific recommendations for RET gene fusions but broadly recommend gene fusion testing via next-generation sequencing (NGS) with RNA.11
  • RNA-based testing has high sensitivity and specificity compared with other forms of testing, and it is generally recommended as the testing methodology for other types of cancers.6,11

RET Targeted Therapy

Approved Agents:

  • One drug—selpercatinib—is currently approved for treating RET gene fusion–positive pancreatic cancer.2,12
  • Selpercatinib received accelerated approval in 2022 for locally advanced or metastatic, tumor-agnostic cancers based on favorable efficacy and safety data.1,2,13 Overall response rate was 44% with a median duration of response of 24.5 months.2,13

Selpercatinib2

  • 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. 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
  2. RETEVMO (selpercatinib). Prescribing information. Eli Lilly and Company. 2024. Accessed June 12, 2024. https://uspl.lilly.com/retevmo/retevmo.html#pi
  3. 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
  4. Ibanez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspecti Biol. 2013;5(2):a009134. doi:10.1101/cshperspect.a009134
  5. Carlomagno F. Thyroid cancer: Role of RET and beyond. Eur Thyroid J. 2012;1(1):15-23. doi:10.1159/000336975
  6. 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
  7. 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
  8. 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
  9. Zhang T, Wang H, Cai Z, Zhang S, Jiang C. RET rearrangement-positive pancreatic cancer has remarkable response to pralsetinib: a case report. Front Oncol. 2023;13:1078076. doi:10.3389/fonc.2023.1078076
  10. Lian EY, Hyndman BD, Moodley S, Maritan SM, Mulligan LM. RET isoforms contribute differentially to invasive processes in pancreatic ductal adenocarcinoma. Oncogene. 2020;39(41):6493-6510. doi:10.1038/s41388-020-01448-z
  11. 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
  12. Properties of FDA-approved small molecule protein kinase inhibitors: A 2022 update. Pharmacol Res. 2022;175:106037. doi:10.1016/j.phrs.2021.106037
  13. 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