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NTRK
genes, trk proteins
1. Rolfo, et al. Expert Opin Investig Drugs 2015; 2. Ahn, et al. WCLC 2017; 3. Doebele, et al. WCLC 2018; 4. Amatu, et al. ESMO Open 2016
Figure modified from Khotskaya, et al. Pharmacol Therap 2017
• The neurotrophic tyrosine kinase receptors, TRKA, TRKB
and TRKC, are single-pass transmembrane proteins that
function as high affinity receptors for neurotrophins, a family
of proteins that regulate many aspects of neuronal
development and function.
• TRKA, TRKB and TRKC receptors are encoded by the
NTRK1, NTRK2, and NTRK3 genes, which are located on
human chromosomes 1q23.1, 9q21.33, an 15q25.3.
• After embryogenesis, TRK expression is limited primarily to
the nervous system, where these kinases help regulate pain,
proprioception, appetite, and memory.
•
TRK
fusions lead to overexpression of the chimeric protein,
resulting in constitutively active, ligand-independent
downstream signaling.
•
Fusions lead to oncogene addiction regardless of tissue
of origin and may be implicated in up to 1% of all solid
tumors
Pro-survival genes
TRKA
NGF
Ras
Raf
MEK 1/2
ERK 1/2
PLCγ
Ca
2+
PKCγ
PI3K
AKT
P
P
P
P
TRKB
BDNF or NT-4/5
P
P
P
P
TRKC
NT-3
P
P
P
P
GSK3
β
S6K1
IκB
Pro-differentiation genes
Synaptic
plasticity
Transcription factors
Regulation of actin
cytoskeleton
Ubiquitin-
mediated
proteolysis