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extracellular domain, a cysteine-rich region, a transmembrane domain, and C-terminal cytoplasmic
tyrosine kinase domain [105] . Under normal conditions, wild-type RET is activated through binding of glial
cell line-derived neurotrophic factor (GDNF) family of ligands [106] and a co-receptor, and it functions
through the modulation of downstream signaling including RAS-MAPK, PI3K-AKT, and phospholipase Cγ
(PLCγ) pathways [107,108] . During development, RET protein plays an important role in the development of
the enteric nervous system [109] and homeostasis of neural, neuroendocrine, hematopoietic, and male germ
tissues [106,110] .

In certain cancers, aberrant, ligand-independent RET activation is associated with gain of function RET
mutations or gene rearrangements (fusions). The first known RET fusion was an in-frame fusion of
CCDC6-RET identified in a patient with papillary thyroid carcinoma [111] . Subsequently, RET fusions were
reported in 13%-43% of papillary thyroid carcinomas [112] , and multiple fusion partners have been reported.
RET fusions mostly occur in irradiation-induced papillary thyroid carcinoma [112] .

The first group of RET fusions in lung cancer, KIF5B-RET, was reported in 2012 [113] with estimated
incidence rates between 1.3% and 6% of lung adenocarcinomas tested. The KIF5B-RET fusion contains RET
kinase domain fused with a coiled-coil domain from KIF5B, which mediates homodimerization and ligand-
independently activates the oncogenic pathways by autophosphorylation. It is also believed that the fusion
event eliminates the auto-inhibitory domain of RET [107,108] . Later studies with much larger samples put the
fusion rate at 1%-2% [114,115] . Interestingly, a review of 936 patients with surgically resected NSCLC suggested
that RET-fusion-positive patients tended to be associated with younger age, never-smoker status, early
lymph node metastases, poor differentiation, and a solid-predominant subtype [116] . Not surprisingly, and
similar to other oncogenic drivers, RET fusions are largely mutually exclusive from other known oncogenic
alterations [117] .

Besides coiled-coil domain-containing protein 6 (CCDC6) and KIF5B, other partners of RET include
nuclear receptor coactivator 4 (NCOA4), the tripartite motif-containing 33 (TRIM33), myosin VC gene
(MYO5C), EPH receptor A5 gene (EPHA5), CAP-Gly domain containing linker protein family member
one gene (CLIP1), ELKS/RAB6-interacting/CAST family member one gene (ERC1), phosphatidylinositol
binding clathrin assembly protein gene (PICALM), FERM domain containing 4A gene (FRMD4A) RUN,
RYVE domain containing two gene (RUFY2), tripartite motif containing 24 gene (TRIM24), tripartite motif
containing 27, and many others. All of these fusion counterparts have a dimerization domain that induces
ligand-independent activation of the RET kinase [118-120] .

In addition to papillary thyroid cancer and lung adenocarcinoma, RET fusions have been identified in other
solid tumors, including colorectal cancer (CRC) [121,122] , breast cancer [121] , and Spitz tumor [45,123] [Table 2].

Given the importance of RET fusions in cancer biology and preclinical support of targeting RET as a
potential intervention agent for cancer [124,125] , multiple selective small molecule kinase inhibitors, such
as RXDX-105 [124] , BLU-667 [126] , and LOXO-292 [127] , have entered clinical development. In the most recent
update [128] , LOXO-292 demonstrated a 68% ORR in RET-fusion-positive NSCLC patients who had
previously received chemotherapy. Additionally, BLU-667 [129] achieved 60% response in second line RET-
fusion-positive NSCLC and 63% response in RET-altered medullary thyroid cancer (MTC) who had
previously been treated with Caprelsa or Cabometyx.

CHALLENGES
Six years ago, Lacombe et al. [130] in their opinion article “The dream and reality of histology agnostic
cancer clinical trials”, while appreciating the need and advantages of tissue-agnostic trials, expressed great
uncertainty whether a true tissue-agnostic approach was feasible and approvable. Six years later, however,