RET

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

RET Biology

  • Discovered in 1985, the RET gene is located on chromosome 10q11.2 and encodes a receptor tyrosine kinase protein, crucial to various cellular processes, including cell growth, proliferation, and differentiation.1,2

Etiology and Epidemiology

  • RET rearrangements were first identified in non–small cell lung cancer (NSCLC) in 2012, and are shown to occur in approximately 1% to 2% of NSCLC cases.3,4
  • These rearrangements function as potent oncogenic drivers through constitutive activation of the RET tyrosine kinase and the downstream signaling pathways MAPK and PI3K/AKT.5-7
  • This leads to increased proliferation of cancer cells and the survival, migration, and invasion of these cells.6
  • RET fusions also enable immune evasion by downregulating major histocompatibility complex class I expression. These tumors tend to have low tumor mutation burden and PD-L1 expression, contributing to poor response to immunotherapy.
  • RET rearrangements confer sensitivity to RET inhibitors (eg, selpercatinib, pralsetinib, cabozantinib), but acquired resistance can develop through secondary RET mutations, alternate pathway activation, or new oncogenic fusions.4,5
  • Over 35 different gene partners have been found in RET fusion, with KIF5B being the predominant one, present in 72% of cases.6,8
  • RET fusion-positive NSCLC is predominantly linked to adenocarcinoma among younger, nonsmoking patients.9

RET Testing

When to Test:

  • All patients with advanced or metastatic lung adenocarcinoma should undergo broad molecular profiling at diagnosis.4
  • Broad molecular profiling should also be considered for those with advanced or metastatic lung squamous cell carcinoma at diagnosis.4
  • In early-stage disease, testing at diagnosis should include assessment of PD-L1, EGFR, and ALK.4

Available Testing Methods:

  • Various methods are available for detecting RET rearrangements, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), reverse-transcriptase polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS).2 
  • While FISH has often been used for detecting RET fusions in NSCLC, there is a risk of false positive due to the frequently occurring RET rearrangements not resulting in functional fusion.14
  • NGS offers greater accuracy, and simultaneous detection of mutations and fusions.2
  • RNA-based NGS is generally preferred to DNA-based NGS for fusion detection owning to the ability of capturing functional fusion irrespective of breakpoint location.4

Guideline Recommendations for Testing:

  • The National Comprehensive Cancer Network NSCLC Panel recommends biomarker testing for RET rearrangements in eligible patients with metastatic NSCLC based on data demonstrating the efficacy of several agents for RET-rearranged NSCLC and FDA approvals for the targeted kinase inhibitors selpercatinib and pralsetinib.4,10-13

RET Targeted Therapy

Approved Agents:

  • The US Food & Drug Administration (FDA) has approved two oral medications for treating RET fusion-positive metastatic NSCLC.
  • Selpercatinib, received accelerated approval in 2020 for use in adult patients with RET fusion-positive metastatic NSCLC on the basis of findings from LIBRETTO-001 and was subsequently granted regular approval on September 21, 2022.17,18
  • More recently, in August 2023, pralsetinib received regular FDA approval for the treatment of adults with RET fusion-positive metastatic NSCLC based on findings from the ARROW trial, following initial accelerated approval in 2020.19,20

Mechanism of Action:

  • Selpercatinib and pralsetinib are RET kinase inhibitors that act by inhibiting wild-type and oncogenic or mutated RET isoforms, thereby suppressing aberrant RET signaling and halting tumor growth in patients with RET-driven cancers.15,16

Learn more about Pralsetinib >

Learn more about Selpercatinib >

References

  1. Li AY, McCusker MG, Russo A, Scilla KA, Gittens A, Arensmeyer K, Mehra R, Adamo V, Rolfo C. RET fusions in solid tumors. Cancer Treat Rev. 2019;81:101911. doi:10.1016/j.ctrv.2019.101911
  2. Reale ML, Bertaglia V, Listì A, Novello S, Passiglia F. Molecular testing and treatment strategies in RET-rearranged NSCLC patients: stay on target to look forward. J Mol Pathol. 2022; 3(1):24-37. doi.org/10.3390/jmp3010003
  3. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18(3):382-384. doi:10.1038/nm.2673
  4. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2024. Accessed March 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
  5. Olmedo ME, Cervera R, Cabezon-Gutierrez L, et al. New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2. World J Clin Oncol. 2022;13(4):276-286. doi:10.5306/wjco.v13.i4.276
  6. Novello S, Califano R, Reinmuth N, Tamma A, Puri T. RET fusion-positive non-small cell lung cancer: the evolving treatment landscape. Oncologist. 2023;28(5):402-413. doi:10.1093/oncolo/oyac264
  7. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol. 2017;35(13):1403-1410. doi:10.1200/JCO.2016.70.9352
  8. Servetto A, Esposito D, Ferrara R, et al. RET rearrangements in non-small cell lung cancer: evolving treatment landscape and future challenges. Biochim Biophys Acta Rev Cancer. 2022;1877(6):188810. doi:10.1016/j.bbcan.2022.188810
  9. Wang R, Hu H, Pan Y, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol. 2012 Dec 10;30(35):4352-4359. doi:10.1200/JCO.2012.44.1477
  10. Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22:959-969. doi:10.1016/S1470-2045(21)00247-3
  11. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653
  12. Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17(12):1653-1660. doi:10.1016/S1470-2045(16)30562-9
  13. Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013;3(6):630-635. doi:10.1158/2159-8290.CD-13-0035
  14. Radonic T, Geurts-Giele WRR, Samsom KG, et al. RET fluorescence in situ hybridization analysis is a sensitive but highly unspecific screening method for RET fusions in lung cancer. J Thorac Oncol. 2021;16(5):798–806. doi:10.1016/j.jtho.2021.01.1619
  15. Retevmo (selpercatinib). Package insert. Eli Lilly and Company; September 2022.
  16. Gravreto (pralsetinib). Package insert. Genentech, Inc; August 2023.
  17. FDA approved selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. US FDA. Updated May 5, 2011. Accessed March 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions
  18. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer. US FDA. Updated September 21, 2022. Accessed March 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-non-small-cell-lung
  19. FDA approves pralsetinib for lung cancer with RET gene fusions. US FDA. Updated September 8, 2020. Accessed March 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions
  20. FDA approves pralsetinib for lung cancer with RET gene fusions. US FDA. Updated September 8, 2020. Accessed March 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pralsetinib-lung-cancer-ret-gene-fusions

Additional Reading

Aldea M, Marinello A, Duruisseaux M, et al. RET-MAP: an international multicenter study on clinicobiologic features and treatment response in patients with lung cancer harboring a RET fusion. J Thorac Oncol. 2023 May;18(5):576-586. doi:10.1016/j.jtho.2022.12.018

Tsuta K, Kohno T, Yoshida A, Shimada Y, Asamura H, Furuta K, Kushima R. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis. Br J Cancer. 2014;110(6):1571-1578. doi:10.1038/bjc.2014.36

Lu C, Zhou Q. Diagnostics, therapeutics, and RET inhibitor resistance for RET fusion-positive non-small cell lung cancers and future perspectives. Cancer Treat Rev. 2021;96:102153. doi:10.1016/j.ctrv.2021.102153

Drusbosky LM, Rodriguez E, Dawar R, Ikpeazu CV. Therapeutic strategies in RET gene rearranged non-small cell lung cancer. J Hematol Oncol. 2021;14(1):50. doi:10.1186/s13045-021-01063-9

Ke JY, Huang S, Jing ZT, Duan MC. The efficacy and safety of selective RET inhibitors in RET fusion-positive non-small cell lung cancer: a meta-analysis. Invest New Drugs. 2023;41(5):768-776. doi:10.1007/s10637-023-01390-3