The Role of Rearrangement During Transfection (RET) Fusions as Oncogenic Drivers

Web Exclusives —December 21, 2020

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Lung Cancer

One example is rearrangement during transfection (RET) fusions, wherein the RET receptor tyrosine kinase fuses with a partner molecule, resulting in oncogenic activity.1-4 RET can be found on the surface of tissues in the nervous system, adrenal medulla, and thyroid, among other tissues.1,5 It plays an important part in renal organogenesis and development of the enteric nervous system as well as in neural crest development.2,6 There are 3 domains in the RET receptor: extracellular domain, transmembrane domain, and intracellular tyrosine kinase domain. Activation of RET requires indirect ligand binding to form a multimeric protein complex.2,7 These ligands (from the glial-derived neurotropic factor [GDNF] family) bind to a GDNF family receptor-alpha,8 with the result mediating RET dimerization and autophosphorylation, which activates RET.7 Upon activation, RET initiates intracellular signaling pathways, including the mitogen‐activated protein kinase, PI3K/AKT, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.1,2 This results in cell proliferation, migration, survival, and differentiation.2,8

Alterations in RET can be associated with a gain or a loss of function. Loss-of-function mutations in RET can result in Hirschsprung’s disease or congenital absence of enteric ganglia.1,2 Gain-of-function changes, including mutations and fusions, have been associated with malignancy.1,2 Chromosomal rearrangements involving RET generate fusion transcripts that pair the 3′ end of RET with the 5′ end of another gene,2 which can result in ligand-independent activation of RET. Because the tyrosine kinase function of RET is preserved in all fusions,2 this results in unchecked cellular proliferation.1,3 Researchers have identified several fusion partners for RET, including CCDC6, NCOA4, PRKAR1A, TRIM24, and KIF5B.1,2

RET fusions are present in 5% to 40% of papillary thyroid cancer. Gain-of-function point mutations are found in up to 50% of patients with medullary thyroid cancer. RET rearrangements manifest in 1% to 2% of patients with non–small-cell lung cancer (NSCLC).2 Germline mutations in RET are present in patients with multiple endocrine neoplasia.3

RET fusions in NSCLC are typically associated with younger patients (<60 years), females, nonsmokers, and of patients of Asian descent.1,8 RET fusion partners identified in NSCLC include KIF5B (the most common fusion partner in NSCLC), CCDC6, TRIM33, and NCOA4. CCDC6, TRIM33, and NCOA4 have also been identified as fusion partners in papillary thyroid cancer.2

There is significant evidence that RET fusions may be meaningful drug targets in NSCLC.1,2 In cell-line studies, treatment of cells expressing the KIF5B-RET fusion with multikinase inhibitors with anti-RET activity results in inhibition of growth.2 Although these agents have modest clinical activity, some selective RET inhibitors have demonstrated significant clinical activity and manageable toxicity.8 As early trials have demonstrated clinically meaningful efficacy, the evidence that RET rearrangements in NSCLC may be treatable with targeted RET inhibitors is encouraging and may represent a significant shift in the treatment of patients with RET-positive NSCLC.8


References

  1. O’Leary C, Xu W, Pavlakis N, et al. Rearranged during transfection fusions in non–small-cell lung cancer. Cancers (Basel). 2019;11:620.
  2. Gainor JF, Shaw AT. Novel targets in non–small-cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18:865-875.
  3. Kato S, Subbiah V, Marchlik E, et al. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23:1988-1997.
  4. Takeuchi K. Discovery stories of RET fusions in lung cancer: mini-review. Front Physiol. 2019;10:216.
  5. Takaya K, Yoshimasa T, Arai H, et al. Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural chest origin. J Mol Med (Berl). 1996;74:617-621.
  6. Ibáñez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5:a009134.
  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;15:151-167.
  8. Ackermann CJ, Stock G, Tay R, et al. Targeted therapy for RET-rearranged non–small-cell lung cancer: clinical development and future directions. Onco Targets Ther. 2019;12:7857-7864.
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