The platelet derived growth factor receptor
alpha (PDGFRA) belongs to a family of receptor
tyrosine kinases (RTKs) that include
PDGFRA and PDGFRB. The binding of ligands, such as platelet derived growth factor (PDGF),
induces a conformational change that facilitates receptor
homo- or heterodimer formation, thereby resulting in activation of PDGFRA tyrosine kinase activity. Activated PDGFRA then
phosphorylates its substrates, resulting in activation of multiple downstream pathways
within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival,
and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).
Mutant PDGFRA has been implicated in the pathogenesis of a number of cancers. For example,
mutations are found in gastrointestinal
stromal tumors (GIST; Corless
et al. 2005; Heinrich et al. 2003), and
fusions are found in hypereosinophilic syndrome (Cools et al.
2003). In dermatofibrosarcoma protuberans, PDGFRA is activated by a PDGFB fusion
protein; as a result, imatinib, as a PDGFRA inhibitor, has shown activity and is approved
for clinical use (Labropoulos
and Razis 2007; Simon et al. 1997).
Figure 1. Schematic of PDGFRA signaling pathways. The binding of the
ligand, platelet-derived growth factor (PDGF), to the PDGFRA receptor tyrosine kinase
results in activation of the MAPK signaling pathway
(RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema
denotes the tyrosine kinase domain.
Suggested Citation: Maki, R., V. Keedy. 2016. PDGFRA. My Cancer Genome
(Updated May 26).
Last Updated: May 26, 2016
PDGFRA in GIST
PDGFRA is mutated in ~5% of GIST, most frequently in gastric GIST. Specifically,
PDGFRA mutations are found mostly
in exons 18 (tyrosine kinase 2 (TK2)
domain; ~5%), 12 (juxtamembrane domain; 1%) and 14 (tyrosine kinase 1 (TK1) domain; <1%). Mutations except for D842V in exon 18 are sensitive to
imatinib (Corless et
Suggested Citation: Maki, R., V. Keedy. 2015. PDGFRA in GIST. My Cancer
Genome https://www.padiracinnovation.org/content/disease/gist/pdgfra/ (Updated
Last Updated: June 18, 2015
No Mutation Detected in KIT, PDGFRA and BRAF in GIST
GISTs with no detected mutations in
KIT, PDGFRA, and BRAF were formerly referred to as wild type; more
precisely, wild type refers to those GISTs that do not have mutations in KIT, PDGFRA,
and BRAF. A significant proportion of GISTs without other mutations have mutations
instead in genes encoding the protein succinate dehydrogenase (SDH), most commonly SDHB
(Janeway et al. 2010)
or SDHA. Approximately half of people with no KIT, PDGFRA, and BRAF
mutations detected in their metastatic GIST have stable disease for ≥ 6 months when
treated with second line sunitinib (Heinrich et al. 2008).
Furthermore, people who get worse despite imatinib and sunitinib for their metastatic GIST,
regorafenib is useful, whether or not there are KIT, PDGFRA, and BRAF
et al. 2013).
Of note, “no mutation detected”
means that tumors were tested for one or more mutations
in one or more genes and none of these
specific mutations were detected. “No
mutation detected” is sometimes
referred to as “wild type.” However, these two terms do not refer to precisely
the same thing. Strictly speaking, the mutation
status should be qualified based on the testing method used. For example, if the testing
only included amino acid V600 in
BRAF and no mutation was detected, then the BRAF mutation status for that
tumor would be "wild type at amino acid V600." Since we now know more about mutations in
genes other than KIT, PDGFRA, and BRAF, the “wild type”
terminology is out of date.
One year of adjuvant imatinib does not improve relapse free survival for people with GISTs
that have no KIT, PDGFRA, and BRAF mutations, p=0.6 (Corless et
al. 2010). For people with no KIT, PDGFRA, and BRAF
mutations detected in GIST in the high-risk category (i.e., > 5 cm, > 5/50 HPF
mitotic count), there may be some benefit of 3 years compared to 1 year of adjuvant
imatinib; however, too few people were included to make a definitive recommendation, HR
0.41, p=0.1 (Joensuu
et al. 2011).
Note that this page is cross-listed under BRAF no mutation detected and KIT no mutation detected in
Suggested Citation: Maki, R., V. Keedy. 2014. No Mutation Detected in KIT, PDGFRA and BRAF in GIST. My Cancer
(Updated October 21).
Last Updated: October 21, 2014
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