RET

Rearranged during transfection (RET)

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 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

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

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 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. 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.pd f
  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