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
  • Mechanism of Action: Selpercatinib binds to and inactivates wild-type RET, RET mutant isoforms, VEGFR1, VEGFR2, and FGFR1-3.2

Learn more about Selpercatinib >

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