• What is PDGFRA?
  • PDGFRA in GIST
  • PDGFRA No Mutation Detected
  • Clinical Trials

PDGFRA

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. 2005Heinrich 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).

 

pdgfra.png

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.

Related Pathways

Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2016. PDGFRA. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/pdgfra/?tab=0 (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 al. 2005).

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Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2015. PDGFRA in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/pdgfra/ (Updated June 18).

Last Updated: June 18, 2015

No Mutation Detected in KIT, PDGFRA and BRAF in GIST

Properties
Location of mutation N/A
Frequency of no mutation detected in KIT/PDGFRA/BRAF in GIST 12–15% (Heinrich et al. 2003)
Implications for Targeted Therapeutics
Response to imatinib Confers decreased sensitivity
Response to sunitinib Some evidence of activity
Response to sorafenib Some evidence of activity (Kindler et al. 2011)
Response to nilotinib Unknown at this time
Response to regorafenib Evidence of activity (Demetri et al. 2013)
Response to dasatinib Some evidence of activity (Schittenhelm et al. 2006; Trent et al. 2011)

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 mutations (Demetri 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 GIST.

Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2014. No Mutation Detected in KIT, PDGFRA and BRAF in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/pdgfra/57/ (Updated October 21).

Last Updated: October 21, 2014

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