RET

Rearranged during transfection proto-oncogene (RET)

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 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

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 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

RET Targeted Therapy

The US Food & Drug Administration (FDA) has approved two oral medications for treating RET fusion-positive metastatic NSCLC. Both approved agents 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 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

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