RET RTK has critical roles in normal kidney and enteric nervous
system development and in the maintenance of several adult tissue
germ cell tissues.1
RET RTK is the receptor for ligands belonging to the GFL. The GFL are
composed of GDNF, neurturin, persephin, and artemin. These ligands
are not able to bind RET on their own, but require a ligand-binding
subunit acting as a co-receptor, known as GFRα co-receptors.
During RET activation, the GFL bind to 4 different GFRα
GFL–GFRα complex induces RET homodimerization,
which activates intracellular kinase domains. This action results in
RET receptor autophosphorylation and subsequent downstream
activation of signal transduction pathways responsible for
can be altered by 2 primary mechanisms
rearrangements that fuse the RET kinase domain with a partner
protein dimerization domain producing hybrid proteins with
mutations that directly or indirectly activate the RET kinase.6-8
alterations in the RET gene are implicated in the pathogenesis
of several human cancers. For RET, fusions and mutations are
the key alterations.7
The term RET-altered cancers encompasses RET-fusions
and RET-mutations, as described in Table
1. RET-Altered Cancers1,9,10
abnormalities that occur when the RET gene becomes fused
with another unrelated gene.
The hybrid gene no longer
functions normally, which can lead to an overproduction of
abnormal RET proteins that are turned on all of the time,
leading to uncontrolled cell growth.
abnormalities that occur when a small change in the RET
gene alters the function of the protein, causing uncontrolled cell
of papillary and other thyroid cancers
of pancreatic cancer, salivary gland cancer, Spitz cancer, CRC,
ovarian cancer, myeloproliferative disorder
to be limited to MTC, with approximately
in sporadic MTC, and
in hereditary MTC.
CCDC6 = coiled-coil domain containing 6; CRC = colorectal cancer;
KIF5B = kinesin family member 5B; MTC =
medullary thyroid cancer; NCOA4 = nuclear receptor coactivator 4;
NSCLC = non-small cell lung cancer; RET = rearranged during
1. A detailed visual representation of the mechanism of disease of
RET-altered cancers may be accessed by clicking here.
Drilon A, Hu ZI, Lai GG, et al. Targeting RET-driven cancers:
lessons from evolving preclinical and clinical landscapes. Nat Rev
Clin Oncol. 2018;15(3):151-167.
Romei C, Ciampi R, Elisei, R. A comprehensive overview of the role
of the RET proto-oncogene in thyroid carcinoma. Nat Rev
Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung
adenocarcinoma. Nat Med. 2012;18(3):375-377.
Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in
lung cancer. Nat Med. 2012;18(3):378-381.
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. https://doi.org/10.1038/nm.2673
Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET
proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet.
Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the
RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature.
Hofstra RM, Landsvater I, Ceccherini I, et al. A mutation in the RET
proto-oncogene associated with multiple endocrine neoplasia type 2B
and sporadic medullary thyroid carcinoma. Nature.
Pietrantonio F, Di Nicolantonio F, Schrock AB, et al. RET fusions in
a small subset of advanced colorectal cancers at risk of being
neglected. Ann Oncol. 2018;29(6):1394-1401.
Su X, He C, Ma J, et al. RET/PTC rearrangements are associated with
elevated postoperative TSH levels and multifocal lesions in papillary
thyroid cancer without concomitant thyroid benign disease. PLoS
= glial cell derived neurotrophic factor
= glial cell derived neurotrophic factor family ligands
= glial cell derived neurotrophic factor family receptor alpha
= rearranged during transfection
= receptor tyrosine kinase
medicinal product is subject to additional monitoring. This will
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professionals are asked to report any suspected adverse reactions.